CNS drugs最新文献

The aim of this article is to review the neurobiological changes associated with methamphetamine use disorder (MUD) and consider what implications they have for the development of effective pharmacotherapies. Novel pharmacotherapies are urgently needed to address the complex neurobiological changes that occur both during and after MUD. Current approaches are modelled on maintenance therapies for opioid use, particularly with the use of prescription stimulant medications to substitute for illicit methamphetamine. Existing evidence suggests that these have limited effectiveness, and enthusiasm has been dampened by concerns about the risk of toxicity. We identify an opportunity to look beyond maintenance therapies and to consider alternative models of pharmacotherapy that support the initiation and maintenance of abstinence. In doing this, we highlight the complexity of the neurobiological changes that occur both during and after cessation of methamphetamine use. We identify a need for pharmacotherapies that can address the lasting neurobiological changes from long-term methamphetamine use to improve treatment engagement and retention as well as functional recovery and to reduce relapse risk.

Background: Agitation is a common and distressing neuropsychiatric symptom in Alzheimer's disease (AD), affecting up to half of patients and contributing to faster cognitive decline and caregiver burden. Brexpiprazole, a serotonin-dopamine modulator, has been evaluated for this indication, but uncertainties remain regarding its efficacy, safety, and appropriate use in older adults.

Objective: We aimed to assess the efficacy and safety of brexpiprazole for the treatment of agitation in older adults with AD through a systematic review and meta-analysis of randomized controlled trials (RCTs).

Methods: Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines and the Cochrane Handbook, we included RCTs comparing brexpiprazole (0.5-3 mg/day) with placebo in older adults with a clinical diagnosis of AD. Primary outcomes were agitation severity (measured using the Cohen-Mansfield Agitation Inventory [CMAI]), clinical impression (clinical global impression-severity scale [CGI-S]), neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI]), and adverse events. Risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) were pooled using a random-effects model. Random-effects meta-analyses were performed using frequentist and Bayesian models in R (version 4.3.0).

Results: A total of five RCTs (N = 1770) met the inclusion criteria. Brexpiprazole was associated with a modest reduction in agitation CMAI (MD - 5.79; 95% CI - 9.55 to - 2.04; prediction interval: - 14.07 to 2.49) and improved CGI-S scores (MD - 0.23; 95% CI - 0.32 to - 0.13; prediction interval: - 0.39 to - 0.06). No significant differences were found in NPI scores. Adverse events such as extrapyramidal symptoms and daytime somnolence occurred more frequently with brexpiprazole but with wide and nonsignificant intervals. Meta-regression did not identify dose or duration as effect modifiers.

Conclusions: Brexpiprazole may offer modest short-term benefits for agitation in AD without cognitive worsening, but safety signals remain imprecise. However, prediction intervals indicate considerable uncertainty, and its use should be individualized and closely monitored. Future trials should prioritize long-term outcomes and patient-centered measures.

Registration prospero protocol number: CRD 42025646060.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting both upper and lower motor neurons. ALS is classically characterized by painless progressive weakness, causing impaired function of limbs, speech, swallowing, and respiratory function. The disease is fatal within 2-4 years, often the result of respiratory failure. The pathologic hallmark for a majority of ALS cases is aberrant cytoplasmic accumulations of the nuclear protein TAR-DNA binding protein (TDP-43). A total of 10-15% of ALS can be attributed to a single gene mutation, known as genetic or "familial" ALS, while the remainder of cases are termed nongenetic or "sporadic" although heritability has been measured in up to 37% in this population. Complex interactions between genetics, environment, and physiologic susceptibility are thought to contribute to disease. Management is primarily supportive in nature, though there are several approved treatments worldwide. This review details the mechanisms and evidence of approved disease-modifying treatments, relevant measures to track disease burden and progression used in clinical trials, and approaches to pharmacologic management of common symptoms in ALS. As there is not currently a cure for ALS, research into the complex pathophysiologic and genetic alterations contributing to disease is of great interest. This review further discusses the current understanding of genetic etiologies and altered physiology leading to disease, such as neuroinflammation, integrated stress response, aberrant proteostasis and mitochondrial dysfunction, among others. The translation of preclinical discoveries into current investigational therapeutics, novel therapeutic categories such as antisense oligonucleotides and stem cell transplantation, as well as future horizons harnessing the power of artificial intelligence in drug development and clinical trials are discussed.

Background: Prolactin increase is a common and potentially problematic adverse event of antipsychotics. We aimed to discover the relationship between antipsychotic doses and changes in prolactin levels.

Objective: To examine the relationship between antipsychotic doses and changes in prolactin levels in adults with acutely exacerbated schizophrenia.

Methods: We searched the Cochrane Schizophrenia Group register (last search 26 July 2024) and previous reviews for fixed-dose, randomized controlled trials (RCTs) that investigated monotherapy of 21 antipsychotics in adults with acutely exacerbated schizophrenia. The primary outcome was mean prolactin change from baseline to study endpoint adopting mean differences (MD) in ng/mL as the effect size measure. The dose-response curves were estimated by conducting random-effects dose-response meta-analyses using the restricted cubic spline method.

Results: Among 165 eligible studies, 68 studies with 238 dose arms (23,128 participants, 35% female) reported on prolactin and were meta-analyzed. Of these, 94% lasted ≤ 3 months, and 90% of the studies used oral formulations. Participants in one study experienced their first episode, while all other studies also included multiepisode participants. The dose-response curves indicated that with aripiprazole, higher doses were significantly associated with lower prolactin levels than lower doses. Brexpiprazole, cariprazine, lumateperone, and quetiapine carried negligible risks for prolactin increase across examined doses. During treatment with most other antipsychotics, i.e., asenapine, haloperidol, iloperidone, lurasidone, olanzapine, paliperidone, risperidone, and ziprasidone, prolactin levels rose with increasing doses and then continued to increase or plateaued. The shape of the dose-response curves was similar in males and females, with generally larger amplitudes of the curves in females.

Conclusions: The prolactin-increasing property varies among antipsychotics, is dose-related, and is greater in females. These findings in adults with acutely exacerbated schizophrenia can help clinicians titrate and adapt antipsychotic doses and consider patients' sex in treatment decisions. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO); registration no. CRD42020181467.

Background and objective: In clinical trials of patients with Lennox-Gastaut syndrome (LGS), a ≥ 50% reduction in drop seizure frequency is generally accepted as a key endpoint. However, smaller reductions (< 50%) may yet be impactful for patients in real-world settings. This exploratory analysis evaluated the threshold for a clinically important response in drop seizures that is associated with the Caregiver Global Impression of Change (CGIC) scale score in patients with LGS treated with cannabidiol (CBD) oral solution and assessed the suitability of CGIC as an anchor for meaningful change.

Methods: This exploratory post hoc analysis included patients with LGS (N = 215, age 2-55 years) receiving CBD (Epidiolex^® [USA]/Epidyolex^® [EU]; 100 mg/mL oral solution) in two phase 3 randomized placebo-controlled trials (NCT02224690, April-October 2015, and NCT02224560, June- December 2015). Reduction in drop seizures (involving sudden loss of muscle tone) was anchored to CGIC scores of "slightly improved" or better or "much improved" or better, to determine the threshold at which seizure reduction can be considered clinically meaningful to patients. Spearman's correlation indicated suitability of anchors (absolute value ≥ 0.30 deemed appropriate).

Results: In the 215 patients receiving CBD with a CGIC score recorded, CGIC was "slightly improved" or better in 60% of patients, and "much improved" or better in 31% after 14 weeks of treatment. With a CGIC rating of "slightly improved" or better, the best threshold for a clinically important response in drop seizure reduction was - 30.6% (57.7% of patients). Mean and median percentage reductions in drop seizures were - 46.9% and - 58.6%, respectively. Using "much improved" or better, the best threshold was - 49.6% (40.5% of patients). Mean and median percentage reductions in drop seizures were - 57.6% and - 66.0%, respectively. Spearman's correlation was 0.47.

Conclusion: Anchoring to CGIC of "slightly improved" or better, the threshold for a clinically meaningful reduction in drop seizure frequency was 31%, suggesting that a 50% cutoff may overlook patients with meaningful improvements in their overall condition, as perceived by their caregivers. CGIC scores, although potentially less nuanced than other standardized clinical assessments, were appropriate anchors to determine thresholds. This exploratory analysis may help contextualize clinical trial data to better understand potential patient benefit attained by reductions in drop seizure frequency observed in real-world settings that are < 50%.

Clinical trials registration numbers: NCT02224560 and NCT02224690.

Dravet syndrome is a severe developmental and epileptic encephalopathy characterized by drug-resistant seizures and multiple nonseizure comorbidities. While disease management has mainly focused on seizure control, there is growing recognition of the importance of nonseizure outcomes in treatment evaluation. This review examines evidence for treatment effects on key nonseizure domains including cognitive functioning, adaptive behavior, speech and language, neurobehavior, sleep, motor outcomes, orthopedic sequelae, nutrition/growth, and quality of life. There is limited evidence following anti-seizure medication trials suggesting improvements in executive function, particularly in preschool-aged children, though findings are inconsistent across studies. Sodium channel blockers are contraindicated, with evidence linking their use to cognitive decline and reduced quality of life. For neurobehavioral symptoms, pharmacological and nonpharmacological treatments show promise in reducing ADHD and behavioral difficulties. Sleep disturbances affect most patients, but evidence for melatonin efficacy is limited. Motor impairments are common, including delayed development, gait abnormalities, and decreased mobility and limited evidence suggests improvements with pharmacological treatment for parkinsonian symptoms. Orthopedic complications include scoliosis, while feeding difficulties may necessitate gastrostomy tube placement. Quality of life measures indicate significant impact from nonseizure symptoms, with evidence of improvement with anti-seizure medication treatment. Overall, findings are limited by small sample sizes, heterogeneous outcome measures, and over-reliance on caregiver reporting. There is a significant knowledge gap regarding disease comorbidities, and future research should investigate nonseizure outcomes alongside seizure control in interventional studies. Dravet syndrome research will benefit from the development of standardized tools validated in the DS population, and establish a core set of outcome measures, prioritized by families, clinicians and researchers to enable meaningful comparison across studies.

Background and objective: Older adults with dementia are particularly vulnerable to antipsychotic side effects. Brexpiprazole, an atypical antipsychotic, is approved in a number of countries for the treatment of agitation associated with dementia due to Alzheimer's disease. This pooled analysis aimed to evaluate the safety and tolerability of brexpiprazole in this patient population.

Methods: Data were included from three Phase 3, 12-week, randomized, double-blind, placebo-controlled trials and a Phase 3, 12-week, active-treatment extension trial in participants with agitation associated with dementia due to Alzheimer's disease. Safety outcomes included treatment-emergent adverse events (TEAEs), weight change, suicidality, extrapyramidal symptoms, and cognitive dysfunction. Two datasets were considered: a 12-week dataset that pooled data from the three randomized trials for brexpiprazole 0.5-3 mg/day and placebo, and a 24-week dataset that combined data from the parent randomized trial and the extension trial for brexpiprazole 2-3 mg/day.

Results: Over 12 weeks, 335/655 (51.1%) participants on brexpiprazole and 178/388 (45.9%) participants on placebo reported ≥ 1 TEAE, which led to discontinuation in 41 (6.3%) and 13 (3.4%) participants, respectively. Headache was the only TEAE with incidence ≥ 5% (brexpiprazole, 50 [7.6%] participants; placebo, 36 [9.3%] participants). The incidences of cerebrovascular TEAEs (brexpiprazole, 0.5%; placebo, 0.3%), cardiovascular TEAEs (3.7%; 2.3%), extrapyramidal symptom-related TEAEs (5.3%; 3.1%), and somnolence/sedation TEAEs (3.7%; 1.8%) were generally similar between treatment groups. Six (0.9%) participants on brexpiprazole and 1 (0.3%) participant on placebo died; causes of death were not considered related to brexpiprazole and were generally in line with those expected in Alzheimer's disease. Over 24 weeks, 110/226 (48.7%) participants on brexpiprazole reported ≥ 1 TEAE, which led to discontinuation in 19 (8.4%) participants. Headache was the only TEAE with incidence ≥ 5% (18 [8.0%] participants). No participants died during the extension trial. Over 12 and 24 weeks, mean changes in weight, suicidality, and extrapyramidal symptoms were minimal, with no worsening of cognition.

Conclusions: Considering pooled data from > 1000 participants on brexpiprazole or placebo, brexpiprazole appears to be generally well tolerated for up to 24 weeks in participants with agitation associated with dementia due to Alzheimer's disease.

Study registration: ClinicalTrials.gov identifiers: NCT01862640, NCT01922258, NCT03548584, NCT03594123.

Background: The efficacy and tolerability of vortioxetine tablets for depression is established, but prospective data for the oral drop formulation were unavailable. This analysis compared the effectiveness, tolerability and dosing patterns of vortioxetine tablet and drop formulations for the treatment of major depressive episodes in Swiss real-world practice.

Methods: A post hoc analysis of a prospective, non-interventional study in adults experiencing a major depressive episode (MDE) was conducted. Depression symptoms, functioning, dosing patterns and tolerability were assessed using unanchored Montgomery-Åsberg Depression Rating Scale items, the Clinical Global Impression-Severity (CGI-S) scale, a four-point functioning scale, and incidence of adverse drug reactions (ADRs). Statistical tests included two-sample t-tests, Fisher's exact test, Chi-square test and general linear modelling.

Results: Of 225 patients, 60 (26.7%) initiated drops. Drops were more often prescribed for first MDE than tablets (65.0% [n = 39] versus 46.1% [n = 76]; p = 0.012) and shorter MDE duration at baseline (2.9 versus 4.8 months; p = 0.02). Mean CGI-S baseline scores were similar (drops: 5.0; tablets: 4.8). Both formulations improved depressive symptoms and functioning similarly. Drops were used in lower initial doses (4.2 mg/day) versus tablets (7.7 mg/day) (p < 0.001) but in higher doses (> 10 mg/day) earlier during treatment (35% versus 13%, day 15). 'No or little effect' was significantly less frequent with drops (5.0%; n = 3) versus tablets (23.6%; n = 39) (p < 0.001). ADR-related discontinuations were comparable (drops: 3.3%; tablets: 4.2%).

Conclusions: This real-world analysis suggests that vortioxetine drops provide comparable control of depressive symptoms to tablets. The greater capacity for dose individualisation may be beneficial to patients.