CNS drugs最新文献

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.

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.

Background and objective: 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.

Methods: 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).

Results: 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].

Conclusions: Cariprazine was observed as efficacious across retrieved studies, offering a potential for tailored treatments across the psychosis spectrum.

Registration number: https://osf.io/pmyhq .

Background and objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Trial registration: ClinicalTrials.gov identification NCT04406649.

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^®) 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^® 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.

Ozanimod (Zeposia^®), an orally administered sphingosine 1-phosphate (S1P) receptor modulator (S1PRM) that is selective for the S1P₁ and S1P₅ 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.

Background and objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Registration: Clinicaltrials.gov Registration (NCT03772314) 12/10/18. .

Background and objective: Viloxazine ER (extended-release capsules; Qelbree^®) is a nonstimulant medication that has been approved by the United States Food and Drug Administration (FDA) for treatment of attention-deficit/hyperactivity disorder (ADHD) in children (> 6 years old) and adults. This phase 3 open-label extension to a pivotal phase 3, double-blind trial evaluated the long-term safety and continued efficacy of viloxazine ER in adults with ADHD.

Methods: This was a multicenter, flexible-dose, open-label extension to a phase III, double-blind, placebo-controlled trial (NCT04016779). Viloxazine ER was initiated at 200 mg/day and adjusted (between 200 and 600 mg/day) to achieve optimal efficacy and tolerability. Trial enrollment was halted temporarily (24 March 2020 to 23 July 2020) due to the coronavirus disease 2019 (COVID-19) pandemic. Participants completing double-blind treatment during that time were offered delayed enrollment upon trial requalification. Safety outcomes were the primary objectives. Secondary objectives were efficacy outcomes, including the ADHD Investigator Symptom Rating Scale (AISRS), and were assessed relative to double-blind baseline (or trial re-entry baseline for those whose enrollment was delayed by the COVID-19 pandemic).

Results: Overall, 159 participants (133 immediate and 26 delayed rollover) received viloxazine ER, with a mean exposure of 265 ± 254.9 days. Adverse events (AEs) included (> 10% incidence) insomnia (13.8%), nausea (13.8%), headache (10.7%), and fatigue (10.1%). AEs led to discontinuation for 17.6% of participants [most commonly insomnia (2.5%), nausea (2.5%), and fatigue (1.9%)]. AISRS total score [baseline mean ± standard deviation (SD): 37.9 ± 6.3] improved by the first follow-up visit (-11.4 ± 9.5; week 2) with continued improvement at subsequent visits (last on-study visit: -18.2 ± 11.54). Similar patterns of improvement were seen for other measures of efficacy, including quality of life and executive function. Following initial dose optimization, most participants (73%) used viloxazine ER doses ≥ 400 mg/day, with 36% using doses of 600 mg/day.

Conclusions: Long-term viloxazine ER use was well tolerated, with no new long-term safety findings. Improvements in ADHD symptoms and associated measures were sustained throughout trial participation. In total, 73% percent of adult participants in this long-term study used viloxazine ER doses of 400 mg or more during maintenance treatment.

Clinical trial registration: Clinicaltrials.gov Identifier: NCT04143217.