CNS drugsPub Date : 2024-12-01Epub Date: 2024-10-08DOI: 10.1007/s40263-024-01123-x
Ruyun Liu, Ning Liu, Lin Ma, Yue Liu, Zhuo Huang, Xiaodong Peng, Chunlin Zhuang, Jianguo Niu, Jianqiang Yu, Juan Du
{"title":"Research Progress on NMDA Receptor Enhancement Drugs for the Treatment of Depressive Disorder.","authors":"Ruyun Liu, Ning Liu, Lin Ma, Yue Liu, Zhuo Huang, Xiaodong Peng, Chunlin Zhuang, Jianguo Niu, Jianqiang Yu, Juan Du","doi":"10.1007/s40263-024-01123-x","DOIUrl":"10.1007/s40263-024-01123-x","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a severe mental illness with a complex etiology. Currently, many medications employed in clinical treatment exhibit limitations such as delayed onset of action and a high incidence of adverse reactions. Therefore, there is a pressing need to develop antidepressants that exhibit enhanced efficacy and safety. The N-methyl-D-aspartate receptor (NMDAR), a distinctive glutamate-gated ion channel receptor, has been implicated in the onset and progression of depressive disorder, as evidenced by both preclinical and clinical research. The NMDAR antagonist, ketamine, exhibits rapid and sustained antidepressant effects, holding promise as a novel therapeutic approach for depressive disorder. However, its psychotomimetic impact and potential for addiction have restricted its widespread clinical application. Notably, over the past decade, studies have suggested that enhancing NMDAR functionality can produce antidepressant effects with improved safety, especially with the emergence of NMDAR-positive allosteric modulators (PAMs). We view this as a potential novel strategy for treating depression, forming the basis for the narrative review that follows.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"985-1002"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388643","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":"A Multicenter, Open-Label Study to Evaluate the Long-term Safety and Efficacy of Adjunctive Brexpiprazole 2 mg Daily in Japanese Patients with Major Depressive Disorder.","authors":"Masaki Kato, Masako Shiosakai, Kazuo Kuwahara, Katsuhiro Iba, Yuki Shimada, Mizuki Saito, Daisuke Sekine, Kazuo Aoki, Yuki Shiomi, Teruhiko Higuchi","doi":"10.1007/s40263-024-01124-w","DOIUrl":"10.1007/s40263-024-01124-w","url":null,"abstract":"<p><strong>Background and objective: </strong>Inadequate response to antidepressant monotherapy is common among patients with major depressive disorder (MDD). The efficacy and safety of adjunctive brexpiprazole 2 mg/day has recently been confirmed during the 6-week, randomized, placebo-controlled phase 2/3 (BLESS) study, which evaluated brexpiprazole at 1 mg/day and 2 mg/day versus placebo as adjunctive therapy to antidepressant therapies in 740 Japanese patients with MDD and an inadequate response to antidepressant monotherapy. This study evaluated the long-term safety and efficacy of adjunctive fixed-dose brexpiprazole 2 mg/day in Japanese patients with MDD.</p><p><strong>Methods: </strong>An open-label, 52-week study enrolled rollover patients who completed the 6-week, double-blind, randomized, placebo-controlled phase 2/3 BLESS study (NCT03697603), and de novo patients aged ≥ 65 years. Patients were titrated to fixed-dose brexpiprazole 2 mg/day from Week 1. Safety assessments included treatment-emergent adverse events (TEAEs; primary outcome) and clinical and laboratory variables. Efficacy was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression-Improvement (CGI-I) scale, Hamilton Depression Rating Scale (HAM-D) 17-item total score, and Sheehan Disability Scale (SDS) score.</p><p><strong>Results: </strong>In total, 247 patients [rollover, n = 216; de novo (previously unexposed), n = 31] were included in the safety/efficacy populations, and 138 (rollover, n = 132; de novo, n = 6; 55.9%) completed the study. Common TEAEs (incidence ≥ 10%) were weight gain [33.2% (n = 82)], akathisia [23.5% (n = 58)], nasopharyngitis [21.1% (n = 52)], and somnolence [10.5% (n = 26)]. TEAEs leading to treatment discontinuation occurred in 26.7% of patients receiving brexpiprazole and 58.1% of de novo patients. The mean (SD) increase in body weight from baseline to Week 52 [observed cases (OC)] was 4.2 (6.5) kg (n = 138); 44.5% (n = 110) had weight gain ≥ 7% at any postbaseline visit. There were no cases of tardive dyskinesia and no AEs related to suicide/suicide attempts. One death occurred (unknown cause), which was unrelated to study treatment. Improvements in the MADRS total score were observed from baseline over the course of the 52-week study [mean (SD) change at Week 52 (OC): - 7.3 (8.7)] for all patients receiving brexpiprazole. The overall MADRS response rate and remission rate in patients receiving brexpiprazole was 41.3% (n = 57) and 34.8% (n = 48), respectively, at Week 52 (OC). Improvements in CGI-S, HAM-D 17 item total score, and SDS mean scores were also observed from baseline over the 52-week study, with a mean (SD) change from baseline at Week 52 (OC) of - 0.8 (1.0), - 5.9 (6.3), and - 1.0 (2.2), respectively, indicating a sustained improvement in symptoms with long-term brexpiprazole treatment.</p><p><strong>Conclusions: </strong>This is the first study to evaluate the safety profile of brexpiprazole 2 ","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"1003-1016"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11543726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459811","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}
CNS drugsPub Date : 2024-12-01Epub Date: 2024-10-21DOI: 10.1007/s40263-024-01130-y
Pavel Klein, Daniel Friedman, Patrick Kwan
{"title":"Recent Advances in Pharmacologic Treatments of Drug-Resistant Epilepsy: Breakthrough in Sight.","authors":"Pavel Klein, Daniel Friedman, Patrick Kwan","doi":"10.1007/s40263-024-01130-y","DOIUrl":"10.1007/s40263-024-01130-y","url":null,"abstract":"<p><p>Epilepsy affects approximately 1% of the world population. Patients have recurrent seizures, increased physical and psychiatric comorbidities, and higher mortality rate than the general population. Over the last 40 years, research has resulted in 20 new antiseizure medications (ASMs) approved between 1990 and 2018. In spite of this, up to one-third of patients (~ 1 million patients in the USA) have drug-resistant epilepsy (DRE), with little change between 1982 and 2018, a period of intense new ASM development. A minority of patients with DRE may benefit from surgical treatment, but this specialized care remains challenging to scale. Therefore, the greatest hope for breakthroughs for patients with DRE is in pharmacologic therapies. Recently, several advances promise to change the outcomes for patients with DRE. Cenobamate, a drug with dual mechanisms of modulating sodium channel currents and GABA-A receptors, achieves 90-100% seizure reduction in 25-33% of patients with focal DRE, a response not observed with other ASMs. Fenfluramine, a serotonin-acting drug, dramatically reduces the frequency of convulsive seizures in Dravet syndrome, a devastating developmental epileptic encephalopathy with severe DRE. Both drugs reduce mortality. In addition, the possibility of DRE prevention was recently raised in patients with tuberous sclerosis complex, a relatively common genetic form of epilepsy. A paradigm shift is emerging in the treatment of epilepsy. Seizure freedom has become attainable in a significant proportion of patients with focal DRE, and dramatic seizure reduction has been achieved in a developmental encephalopathy. Coupled with a rich pipeline of new compounds under clinical development, the long sought-after breakthrough in the treatment of epilepsy may finally be in sight.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"949-960"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459812","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}
CNS drugsPub Date : 2024-12-01Epub Date: 2024-10-09DOI: 10.1007/s40263-024-01125-9
Livio Tarchi, Susan Bugini, Cristiano Dani, Emanuele Cassioli, Eleonora Rossi, Stefano Lucarelli, Valdo Ricca, Saverio Caini, Giovanni Castellini
{"title":"Efficacy of Cariprazine in the Psychosis Spectrum: A Systematic Review and Network Meta-Analysis of Randomised Controlled Trials in Schizophrenia and Bipolar Disorder.","authors":"Livio Tarchi, Susan Bugini, Cristiano Dani, Emanuele Cassioli, Eleonora Rossi, Stefano Lucarelli, Valdo Ricca, Saverio Caini, Giovanni Castellini","doi":"10.1007/s40263-024-01125-9","DOIUrl":"10.1007/s40263-024-01125-9","url":null,"abstract":"<p><strong>Background and objective: </strong>Psychosis represents one of the most challenging clinical presentations in psychiatry. Schizophrenia and bipolar disorder may both present psychotic features, and cariprazine may offer improvement in the treatment and care of these conditions. Therefore, the objective of the current work was to synthesise results of efficacy for cariprazine in these disorders.</p><p><strong>Methods: </strong>In total, five electronic databases were searched for randomized controlled trials enrolling patients across the psychosis spectrum, using the search term 'Cariprazine' (PubMed, Embase, clinicaltrials.gov, EUDRACT, Cochrane-last search January 2024). No filter or limits were employed. Effect sizes were extracted, by the mean difference in psychometric variables before and after the intervention (Clinical Global Impression Scale, Positive and Negative Symptom Scale, Montgomery-Asberg Depression Rating Scale, Young Mania Rating Scale, Hamilton Anxiety Rating Scale).</p><p><strong>Results: </strong>In total, 12 studies enrolling either patients with schizophrenia or bipolar disorder were included (total n = 6477; n = 4814 patients treated with cariprazine, n = 1663 controls treated with placebo). Cariprazine was effective in reducing global clinical severity, and higher improvements were observed at increasing dosages (- 0.25 at ≤ 1.5 mg/day, - 0.45 at ≥ 3 mg/day). Cariprazine also effectively reduced psychotic total scores: - 6.74, [95% confidence interval (CI) - 8.31; - 5.17], depression: - 1.78, [95% CI - 2.54; - 1.02], mania: - 5.72, [95% CI - 6.95; - 4.49], and anxiety symptoms: - 1.24, [95% CI - 1.92; - 0.56].</p><p><strong>Conclusions: </strong>Cariprazine was observed as efficacious across retrieved studies, offering a potential for tailored treatments across the psychosis spectrum.</p><p><strong>Registration number: </strong>https://osf.io/pmyhq .</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"961-971"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11543740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388642","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}
CNS drugsPub Date : 2024-12-01Epub Date: 2024-10-07DOI: 10.1007/s40263-024-01118-8
Stewart J Tepper, Detlef Albrecht, Jessica Ailani, Louis Kirby, Shannon Strom, Alan M Rapoport
{"title":"Long-Term (12-Month) Safety and Tolerability of STS101 (Dihydroergotamine Nasal Powder) in the Acute Treatment of Migraine: Data from the Phase 3 Open-Label ASCEND Study.","authors":"Stewart J Tepper, Detlef Albrecht, Jessica Ailani, Louis Kirby, Shannon Strom, Alan M Rapoport","doi":"10.1007/s40263-024-01118-8","DOIUrl":"10.1007/s40263-024-01118-8","url":null,"abstract":"<p><strong>Background and objective: </strong>STS101 is an investigational drug-device combination comprising 5.2 mg dihydroergotamine (DHE) powder (6.0 mg DHE mesylate) in a single-use nasal delivery device for the acute treatment of migraine. The primary objective of the ASCEND trial was to assess long-term safety and tolerability of STS101 in the acute treatment of migraine attacks across 12-18 months, with secondary objectives describing efficacy.</p><p><strong>Methods: </strong>ASCEND was an open-label study of STS101 in adults aged 18-65 years with a ≥ 1 year history of migraine with or without aura, with onset before the age of 50 years and 4-12 migraine attacks/month and < 15 headache days/month in each of the 3 months prior to screening. Exclusion criteria included diagnosis of non-migraine headache, history of cerebrovascular disease, and ≥ 2 cardiovascular risk factors. After establishing eligibility, participants could self-administer STS101 5.2 mg as needed for up to 2 doses within 24 h to treat a single migraine attack and up to 12 doses/month. Safety and tolerability evaluations included physical and nasal examinations, vital signs, laboratory tests, and treatment-emergent adverse event (TEAE) assessments. Participants used an electronic diary to record exploratory efficacy parameters, including intensity of headache pain and associated migraine symptoms (photophobia, phonophobia, and nausea). Participant impression questions were asked at months 3, 6, and 12.</p><p><strong>Results: </strong>Of the 6610 migraine attacks treated with a total of 8234 STS101 doses in 344 participants, 945/6610 (14.3%) were associated with a TEAE. Events were predominantly mild or moderate in nature and rarely led to premature study discontinuation (15/344 [4.4%] participants). Treatment was associated with rapid onset of freedom from pain (36.6%, 67.1%, and 85.5% of treated attacks 2, 4, and 24 h post-dose, respectively), freedom from most bothersome symptoms (54.3%, 79.6%, and 91.3%), and headache relief (66.5%, 89.1%, and 94.3%). Most participants rated treatment results as good or very good and ease of use as easy or very easy at all time points (months 3, 6, and 12) and indicated they were likely or very likely to use STS101 again.</p><p><strong>Conclusions: </strong>The repeated long-term, as-needed use of STS101 was well tolerated, demonstrating a favorable safety profile in the acute treatment of migraine attacks in appropriately indicated adults. Exploratory efficacy evaluations indicated beneficial effects, which warrant further evaluation.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identification NCT04406649.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"1017-1027"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11543709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380213","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 Safety of Antipsychotic Medications and Mood Stabilizers During Pregnancy: A Systematic Review and Network Meta-analysis of Congenital Malformations and Prenatal Outcomes.","authors":"Enhui Wang, Yilin Liu, Yucheng Wang, Xinyu Han, Yifang Zhou, Lingli Zhang, Yanqing Tang","doi":"10.1007/s40263-024-01131-x","DOIUrl":"https://doi.org/10.1007/s40263-024-01131-x","url":null,"abstract":"<p><strong>Background: </strong>A network meta-analysis was performed to evaluate the risk of congenital malformations and other prenatal outcomes in fetuses after exposure to antipsychotic medications and mood stabilizers during pregnancy.</p><p><strong>Methods: </strong>We searched the PubMed, EMBASE, and Cochrane CENTRAL databases up to 15 December 2023, to identify experimental and observational studies comparing antipsychotic and mood stabilizer treatments with control treatments (no exposure). The primary outcome of the study was the incidence of congenital malformations and the secondary outcomes were preterm birth and spontaneous abortion. Additionally, two authors independently assessed the risk of bias in each domain of the included studies using the ROBINS-I tool and evaluated the quality of evidence using the CINeMA rating tool.</p><p><strong>Results: </strong>The literature search identified 18,334 potential records, and 22 studies involving 3,042,997 pregnant women were ultimately included. Compared with the unexposed group, quetiapine [odds ratio (OR), 1.19; 95% credible interval (CrI), 1.01-1.39], aripiprazole (OR, 1.30; 95% CrI 1.10-1.65), olanzapine (OR, 1.33; 95% CrI 1.11-1.64), risperidone (OR, 1.43; 95% CrI 1.18-1.77), and lithium (OR, 1.61; 95% CrI 1.07-2.30) were associated with a slightly increased risk of congenital malformations. In contrast, lamotrigine (OR, 1.21; 95% CrI 0.86-1.64), ziprasidone (OR, 1.14; 95% CrI 0.73-1.72), and haloperidol (OR, 1.26; 95% CrI 0.90-1.75) did not show significant differences compared with the unexposed group, with narrower credible intervals.</p><p><strong>Conclusions: </strong>The evidence from this analysis suggests that, overall, quetiapine has the lowest teratogenic risk when used during pregnancy, making it the safer option for pregnant women. Lamotrigine and haloperidol follow closely behind. At the same time, the use of lurasidone and ziprasidone should be approached with caution, and further clinical studies are necessary to better assess their safety.</p><p><strong>Systematic review registration: </strong>PROSPERO CRD4201811373.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615497","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}
CNS drugsPub Date : 2024-11-09DOI: 10.1007/s40263-024-01127-7
Sherihan Rezk Ahmed, Nevine El Nahas, Mohamed Fouad Elsayed Khalil, Ahmed Elbassiouny, Mohamed Ahmed Almoataz, Tarek Youssif Omar, Ahmed Mohamed Ali Daabis, Hossam Mohamed Refat, Ahmed Ahmed Mohamed Kamal Ebied, Asmaa Mohammed Hassan, Diaa Mostafa Atiaa Mohamed, Mohamed Ismaiel, Mohamed G Zeinhom
{"title":"TICA-CLOP STUDY: Ticagrelor Versus Clopidogrel in Acute Moderate and Moderate-to-Severe Ischemic Stroke, a Randomized Controlled Multi-Center Trial.","authors":"Sherihan Rezk Ahmed, Nevine El Nahas, Mohamed Fouad Elsayed Khalil, Ahmed Elbassiouny, Mohamed Ahmed Almoataz, Tarek Youssif Omar, Ahmed Mohamed Ali Daabis, Hossam Mohamed Refat, Ahmed Ahmed Mohamed Kamal Ebied, Asmaa Mohammed Hassan, Diaa Mostafa Atiaa Mohamed, Mohamed Ismaiel, Mohamed G Zeinhom","doi":"10.1007/s40263-024-01127-7","DOIUrl":"https://doi.org/10.1007/s40263-024-01127-7","url":null,"abstract":"<p><strong>Background: </strong>Many studies evaluated the efficacy and safety of ticagrelor versus clopidogrel in patients with ischemic stroke; none of these trials included North African participants, and all of these trials comprised only participants who experienced transient ischemic attack (TIA) or minor stroke.</p><p><strong>Objectives: </strong>We compared the efficacy and safety of ticagrelor versus clopidogrel in patients with first-ever noncardioembolic moderate or moderate-to-severe ischemic stroke.</p><p><strong>Methods: </strong>Our trial involved 900 first-ever noncardioembolic patients with acute ischemic stroke (AIS) who randomly received either loading and maintenance doses of ticagrelor or clopidogrel within the first 24 h of stroke onset.</p><p><strong>Results: </strong>We involved 900 patients in the intention-to-treat analysis. A total of 39 (8.7%) patients in ticagrelor arm and 62 (13.8%) in clopidogrel arm experienced a new stroke [hazard ratio (HR) 0.46; 95% confidence interval (CI) 0.34-0.83; P value = 0.006]. A total of 57 (12.7%) patients in ticagrelor group and 80 (17.8%) patients in clopidogrel group experienced composite of new stroke, myocardial infarction (MI), or death due to vascular insults (HR 0.51; 95% CI 0.43-0.82; P value = 0.004). Participants who received ticagrelor experienced less frequent unfavorable outcomes. We found no significant variation between our study's two arms concerning the hemorrhagic and non-hemorrhagic complications.</p><p><strong>Conclusion: </strong>Patients with noncardioembolic moderate or moderate-to-severe ischemic stroke who received ticagrelor within the first 24 h after ischemic stroke had better clinical outcomes based on recurrent stroke rates and unfavorable modified Rankin Scale (mRS) rates compared with those who received clopidogrel. There were no significant variations between ticagrelor and clopidogrel regarding hemorrhagic and non-hemorrhagic complications.</p><p><strong>Registration: </strong>ClinicalTrials.gov identifier number NCT05553613.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615528","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}
CNS drugsPub Date : 2024-11-01Epub Date: 2024-08-16DOI: 10.1007/s40263-024-01114-y
Roger S McIntyre, Rakesh Jain
{"title":"Glutamatergic Modulators for Major Depression from Theory to Clinical Use.","authors":"Roger S McIntyre, Rakesh Jain","doi":"10.1007/s40263-024-01114-y","DOIUrl":"10.1007/s40263-024-01114-y","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a chronic, burdensome, highly prevalent disease that is characterized by depressed mood and anhedonia. MDD is especially burdensome as approved monoamine antidepressant treatments have weeks-long delays before clinical benefit and low remission rates. In the past 2 decades, a promising target emerged to improve patient outcomes in depression treatment: glutamatergic signaling. This narrative review provides a high-level overview of glutamate signaling in synaptogenesis and neural plasticity and the implications of glutamate dysregulation in depression. Based on this preclinical evidence implicating glutamate in depression and the rapid improvement of depression with ketamine treatment in a proof-of-concept trial, a range of N-methyl-D-aspartate (NMDA)-targeted therapies have been investigated. While an array of treatments has been investigated in registered phase 2 or 3 clinical trials, the development of most of these agents has been discontinued. Multiple glutamate-targeted antidepressants are actively in development, and two are approved. Nasal administration of esketamine (Spravato<sup>®</sup>) was approved by the US Food and Drug Administration (FDA) in 2019 to treat adults with treatment-resistant depression and in 2020 for adults with MDD with acute suicidal ideation or behavior. Oral combination dextromethorphan-bupropion (AXS-05, Auvelity<sup>®</sup> extended-release tablet) was FDA approved in 2022 for the treatment of MDD in adults. These approvals bolster the importance of glutamate in depression and represent an exciting breakthrough in contemporary psychiatry, providing new avenues of treatment for patients as first-line therapy or with either poor response or unacceptable side effects to monoaminergic antidepressants.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"869-890"},"PeriodicalIF":7.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11486832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987588","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}
CNS drugsPub Date : 2024-11-01Epub Date: 2024-09-21DOI: 10.1007/s40263-024-01122-y
Lynn Marie Trotti, Tyler Blake, Romy Hoque, David B Rye, Surina Sharma, Donald L Bliwise
{"title":"Modafinil Versus Amphetamine-Dextroamphetamine For Idiopathic Hypersomnia and Narcolepsy Type 2: A Randomized, Blinded, Non-inferiority Trial.","authors":"Lynn Marie Trotti, Tyler Blake, Romy Hoque, David B Rye, Surina Sharma, Donald L Bliwise","doi":"10.1007/s40263-024-01122-y","DOIUrl":"10.1007/s40263-024-01122-y","url":null,"abstract":"<p><strong>Background and objective: </strong>Although there are several treatments for narcolepsy type 2 and idiopathic hypersomnia, studies that assess amphetamines, symptoms beyond sleepiness, and comparative effectiveness are needed. We performed a randomized, fully blinded, noninferiority trial of modafinil versus amphetamine-dextroamphetamine in these disorders.</p><p><strong>Methods: </strong>Forty-four adults were randomized to modafinil or amphetamine-dextroamphetamine, individually titrated to a maximum of modafinil 200 mg twice daily or amphetamine-dextroamphetamine 20 mg twice daily, for 12 weeks. Primary outcome was change in Epworth from baseline to week 12, with a noninferiority threshold of 2 points. Secondary outcomes were (1) patient global impression of change measures of disease severity, sleepiness, sleep inertia, and cognition; (2) change from baseline in Hypersomnia Severity Index; and (3) change from baseline in Sleep Inertia Questionnaire. Adverse events were compared between groups.</p><p><strong>Results: </strong>Epworth improved 5.0 [± standard deviation (SD) 2.7] points with modafinil and 4.4 (± SD 4.7) with amphetamine-dextroamphetamine; noninferiority of amphetamine-dextroamphetamine was not demonstrated (P = 0.11). Noninferiority of amphetamine-dextroamphetamine was demonstrated for change scores of severity, sleepiness, sleep inertia, Hypersomnia Severity Index, and Sleep Inertia Questionnaire. Dropouts due to adverse events were 31.8% for modafinil (including two severe events) and 9.1% for amphetamine-dextroamphetamine, P = 0.13. Anxiety was more common with modafinil and appetite suppression with amphetamine-dextroamphetamine.</p><p><strong>Conclusion: </strong>Noninferiority of amphetamine-dextroamphetamine to modafinil was not demonstrated for the primary outcome. However, amphetamine-dextroamphetamine was noninferior on multiple secondary measures of disease severity and symptomatology. These data may inform shared decision-making regarding treatment for idiopathic hypersomnia and narcolepsy type 2.</p><p><strong>Registration: </strong>Clinicaltrials.gov Registration (NCT03772314) 12/10/18. .</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"909-920"},"PeriodicalIF":7.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281509","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}
CNS drugsPub Date : 2024-11-01Epub Date: 2024-10-05DOI: 10.1007/s40263-024-01116-w
Tina Nie, Yahiya Y Syed
{"title":"Ozanimod: A Review in Relapsing Forms of Multiple Sclerosis.","authors":"Tina Nie, Yahiya Y Syed","doi":"10.1007/s40263-024-01116-w","DOIUrl":"10.1007/s40263-024-01116-w","url":null,"abstract":"<p><p>Ozanimod (Zeposia<sup>®</sup>), an orally administered sphingosine 1-phosphate (S1P) receptor modulator (S1PRM) that is selective for the S1P<sub>1</sub> and S1P<sub>5</sub> receptor subtypes, is approved in the USA for relapsing forms of multiple sclerosis (RMS). In pivotal phase III clinical trials in patients with RMS, ozanimod significantly reduced annualised relapse rates and the number of new or enlarging T2 lesions and gadolinium-enhancing lesions, and was associated with reduced brain volume loss, compared with interferon (IFN)-β1a. However, there were no significant differences in 3- and 6-month disability progression between the groups. Ozanimod was generally well tolerated, with the most common adverse reactions including upper respiratory tract infection and hepatic transaminase elevation. Efficacy and tolerability were sustained over more than 6 years with continued treatment. S1PRM-related adverse events seen with ozanimod are generally manageable with screening and/or monitoring. Notably, ozanimod does not require first-dose cardiac monitoring in the USA. In conclusion, ozanimod is a valuable once-daily oral disease-modifying therapy that extends the available treatment options for patients with RMS.</p>","PeriodicalId":10508,"journal":{"name":"CNS drugs","volume":" ","pages":"931-941"},"PeriodicalIF":7.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379197","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}