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International Journal of Molecular... Sep 2023In an ever-increasing aged world, Alzheimer's disease (AD) represents the first cause of dementia and one of the first chronic diseases in elderly people. With 55... (Review)
Review
In an ever-increasing aged world, Alzheimer's disease (AD) represents the first cause of dementia and one of the first chronic diseases in elderly people. With 55 million people affected, the WHO considers AD to be a disease with public priority. Unfortunately, there are no final cures for this pathology. Treatment strategies are aimed to mitigate symptoms, i.e., acetylcholinesterase inhibitors (AChEI) and the N-Methyl-D-aspartate (NMDA) antagonist Memantine. At present, the best approaches for managing the disease seem to combine pharmacological and non-pharmacological therapies to stimulate cognitive reserve. Over the last twenty years, a number of drugs have been discovered acting on the well-established biological hallmarks of AD, deposition of β-amyloid aggregates and accumulation of hyperphosphorylated tau protein in cells. Although previous efforts disappointed expectations, a new era in treating AD has been working its way recently. The Food and Drug Administration (FDA) gave conditional approval of the first disease-modifying therapy (DMT) for the treatment of AD, aducanumab, a monoclonal antibody (mAb) designed against Aβ plaques and oligomers in 2021, and in January 2023, the FDA granted accelerated approval for a second monoclonal antibody, Lecanemab. This review describes ongoing clinical trials with DMTs and non-pharmacological therapies. We will also present a future scenario based on new biomarkers that can detect AD in preclinical or prodromal stages, identify people at risk of developing AD, and allow an early and curative treatment.
Topics: United States; Humans; Aged; Alzheimer Disease; Acetylcholinesterase; Amyloid beta-Peptides; Memantine; Antibodies, Monoclonal
PubMed: 37762203
DOI: 10.3390/ijms241813900 -
BMJ Open Apr 2022To examine the comparative efficacy and safety of cognitive enhancers by patient characteristics for managing Alzheimer's dementia (AD). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To examine the comparative efficacy and safety of cognitive enhancers by patient characteristics for managing Alzheimer's dementia (AD).
DESIGN
Systematic review and individual patient data (IPD) network meta-analysis (NMA) based on our previously published systematic review and aggregate data NMA.
DATA SOURCES
MEDLINE, Embase, Cochrane Methodology Register, CINAHL, AgeLine and Cochrane Central Register of Controlled Trials up to March 2016.
PARTICIPANTS
80 randomised controlled trials (RCTs) including 21 138 adults with AD, and 12 RCTs with IPD including 6906 patients.
INTERVENTIONS
Cognitive enhancers (donepezil, rivastigmine, galantamine and memantine) alone or in any combination against other cognitive enhancers or placebo.
DATA EXTRACTION AND SYNTHESIS
We requested IPD from authors, sponsors and data sharing platforms. When IPD were not available, we used aggregate data. We appraised study quality with the Cochrane risk-of-bias. We conducted a two-stage random-effects IPD-NMA, and assessed their findings using CINeMA (Confidence in Network Meta-Analysis).
PRIMARY AND SECONDARY OUTCOMES
We included trials assessing cognition with the Mini-Mental State Examination (MMSE), and adverse events.
RESULTS
Our IPD-NMA compared nine treatments (including placebo). Donepezil (mean difference (MD)=1.41, 95% CI: 0.51 to 2.32) and donepezil +memantine (MD=2.57, 95% CI: 0.07 to 5.07) improved MMSE score (56 RCTs, 11 619 participants; CINeMA score: moderate) compared with placebo. According to P-score, oral rivastigmine (OR=1.26, 95% CI: 0.82 to 1.94, P-score=16%) and donepezil (OR=1.08, 95% CI: 0.87 to 1.35, P-score=30%) had the least favourable safety profile, but none of the estimated treatment effects were sufficiently precise when compared with placebo (45 RCTs, 15 649 patients; CINeMA score: moderate to high). For moderate-to-severe impairment, donepezil, memantine and their combination performed best, but for mild-to-moderate impairment donepezil and transdermal rivastigmine ranked best. Adjusting for MMSE baseline differences, oral rivastigmine and galantamine improved MMSE score, whereas when adjusting for comorbidities only oral rivastigmine was effective.
CONCLUSIONS
The choice among the different cognitive enhancers may depend on patient's characteristics. The MDs of all cognitive enhancer regimens except for single-agent oral rivastigmine, galantamine and memantine, against placebo were clinically important for cognition (MD larger than 1.40 MMSE points), but results were quite imprecise. However, two-thirds of the published RCTs were associated with high risk of bias for incomplete outcome data, and IPD were only available for 15% of the included RCTs.
PROSPERO REGISTRATION NUMBER
CRD42015023507.
Topics: Adult; Alzheimer Disease; Donepezil; Galantamine; Humans; Memantine; Network Meta-Analysis; Nootropic Agents; Rivastigmine
PubMed: 35473731
DOI: 10.1136/bmjopen-2021-053012 -
Alzheimer's Research & Therapy Feb 2023Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system (mast cells and microglia). Study AB09004 evaluated... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system (mast cells and microglia). Study AB09004 evaluated masitinib as an adjunct to cholinesterase inhibitor and/or memantine in patients with mild-to-moderate dementia due to probable Alzheimer's disease (AD).
METHODS
Study AB09004 was a randomized, double-blind, two parallel-group (four-arm), placebo-controlled trial. Patients aged ≥50 years, with clinical diagnosis of mild-to-moderate probable AD and a Mini-Mental State Examination (MMSE) score of 12-25 were randomized (1:1) to receive masitinib 4.5 mg/kg/day (administered orally as two intakes) or placebo. A second, independent parallel group (distinct for statistical analysis and control arm), randomized patients (2:1) to masitinib at an initial dose of 4.5 mg/kg/day for 12 weeks that was then titrated to 6.0 mg/kg/day, or equivalent placebo. Multiple primary outcomes (each tested at a significance level of 2.5%) were least-squares mean change from baseline to week 24 in the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog), or the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL). Safety for each masitinib dose level was compared against a pooled placebo population.
RESULTS
Masitinib (4.5 mg/kg/day) (n=182) showed significant benefit over placebo (n=176) according to the primary endpoint of ADAS-cog, -1.46 (95% CI [-2.46, -0.45]) (representing an overall improvement in cognition) versus 0.69 (95% CI [-0.36, 1.75]) (representing increased cognitive deterioration), respectively, with a significant between-group difference of -2.15 (97.5% CI [-3.48, -0.81]); p<0.001. For the ADCS-ADL primary endpoint, the between-group difference was 1.82 (97.5% CI [-0.15, 3.79]); p=0.038 (i.e., 1.01 (95% CI [-0.48, 2.50]) (representing an overall functional improvement) versus -0.81 (95% CI [-2.36, 0.74]) (representing increased functional deterioration), respectively). Safety was consistent with masitinib's known profile (maculo-papular rash, neutropenia, hypoalbuminemia). Efficacy results from the independent parallel group of titrated masitinib 6.0 mg/kg/day versus placebo (n=186 and 91 patients, respectively) were inconclusive and no new safety signal was observed.
CONCLUSIONS
Masitinib (4.5 mg/kg/day) may benefit people with mild-to-moderate AD. A confirmatory study has been initiated to substantiate these data.
TRIAL REGISTRATION
EudraCT: 2010-021218-50.
CLINICALTRIALS
gov : NCT01872598.
Topics: Humans; Alzheimer Disease; Activities of Daily Living; Memantine; Thiazoles
PubMed: 36849969
DOI: 10.1186/s13195-023-01169-x -
Proceedings of the National Academy of... Nov 2023Neurotransmitter receptors are increasingly recognized to play important roles in anti-tumor immunity. The expression of the ion channel N-methyl-D-aspartate receptor...
Neurotransmitter receptors are increasingly recognized to play important roles in anti-tumor immunity. The expression of the ion channel N-methyl-D-aspartate receptor (NMDAR) on macrophages was reported, but the role of NMDAR on macrophages in the tumor microenvironment (TME) remains unknown. Here, we show that the activation of NMDAR triggered calcium influx and reactive oxygen species production, which fueled immunosuppressive activities in tumor-associated macrophages (TAMs) in the hepatocellular sarcoma and fibrosarcoma tumor settings. NMDAR antagonists, MK-801, memantine, and magnesium, effectively suppressed these processes in TAMs. Single-cell RNA sequencing analysis revealed that blocking NMDAR functionally and metabolically altered TAM phenotypes, such that they could better promote T cell- and Natural killer (NK) cell-mediated anti-tumor immunity. Treatment with NMDAR antagonists in combination with anti-PD-1 antibody led to the elimination of the majority of established preclinical liver tumors. Thus, our study uncovered an unknown role for NMDAR in regulating macrophages in the TME of hepatocellular sarcoma and provided a rationale for targeting NMDAR for tumor immunotherapy.
Topics: Humans; Tumor-Associated Macrophages; Neoplastic Processes; Memantine; Liver Neoplasms; Sarcoma; Tumor Microenvironment
PubMed: 37967215
DOI: 10.1073/pnas.2302126120 -
Acta Psychiatrica Scandinavica Jul 2023The augmentation of serotonin reuptake inhibitors (SRIs) can be achieved by add-on therapy with different pharmacological agents in obsessive-compulsive disorder (OCD)... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The augmentation of serotonin reuptake inhibitors (SRIs) can be achieved by add-on therapy with different pharmacological agents in obsessive-compulsive disorder (OCD) for a better clinical outcome. This network meta-analysis (NMA) was conducted to evaluate and compare the effects of available augmentation agents for SRIs in OCD.
METHOD
The data was extracted from 59 relevant clinical trials after a literature search on MEDLINE/PubMed, Scopus, Cochrane databases and clinical trial registries. PRISMA guidelines were followed in data extraction, analysis and reporting. Random effects Bayesian NMA was done to pool the effects across the interventions for the change in Yale-Brown Obsessive-Compulsive Scale (YBOCS) scoring from baseline to the end of the study. Network graph was built, consistency model was run, node splitting analysis was performed, treatments were ranked as per SUCRA score and meta-regression was done for refractoriness to SRIs and duration of augmentation therapy as the predictor variables.
RESULTS
The drugs showing significant reduction in YBOCS scoring were pregabalin (MD:-8.1;95% CrI: -16, -0.43), memantine (MD:-6.2;95% CrI: -9.9, -2.3), lamotrigine (MD:-6;95% CrI: -12, -0.47), ondansetron (MD:-5.7;95% CrI: -11, -0.67), granisetron (MD:-5.6;95% CrI: -11, -0.44), aripiprazole (MD:-5.4;95% CrI:-9.1, -1.6), risperidone (MD:-3.3;95% CrI: -6.4, -0.20) and topiramate (MD:-5.3;95% CrI: -9.6, -0.97). The node-split analysis showed that direct and indirect pooled effect sizes for all comparisons were comparable. Meta-regression showed a statistically non-significant association between YBOCS score reduction with the duration of augmentation therapy, but significant with SRI-refractory status. Finally, the results were sorted based on certainty of evidence.
CONCLUSION
Memantine was found to be most effective augmentation agent for SRIs in OCD, followed by lamotrigine, ondansetron and granisetron with moderate certainty of evidence. The augmentation agents showed better symptom reduction in patients with SRI-refractory OCD in comparison to non-refractory OCD.
PROSPERO REGISTRATION
CRD42022360110.
Topics: Humans; Selective Serotonin Reuptake Inhibitors; Ondansetron; Drug Therapy, Combination; Lamotrigine; Network Meta-Analysis; Bayes Theorem; Granisetron; Memantine; Obsessive-Compulsive Disorder; Treatment Outcome
PubMed: 37177823
DOI: 10.1111/acps.13568 -
European Archives of Psychiatry and... Oct 2023This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of... (Review)
Review
This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of the pharmacological class of uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists that have shown efficacy for major depressive disorder (MDD) and other diseases and disorders, such as Alzheimer's dementia and pseudobulbar affect. The other drugs in the novel class of NMDAR antagonists with therapeutic uses that are discussed for comparative purposes in this review are esketamine, ketamine, dextromethorphan, and memantine. We present in silico, in vitro, in vivo, and clinical data for esmethadone and other uncompetitive NMDAR antagonists that may advance our understanding of the role of these receptors in neural plasticity in health and disease. The efficacy of NMDAR antagonists as rapid antidepressants may advance our understanding of the neurobiology of MDD and other neuropsychiatric diseases and disorders.
Topics: Humans; Excitatory Amino Acid Antagonists; Depressive Disorder, Major; Memantine; Antidepressive Agents; Alzheimer Disease
PubMed: 36890259
DOI: 10.1007/s00406-023-01571-4 -
Psychopharmacology Bulletin Jul 2023Introduction The purpose of this guide is to provide convenient and useful information on about Alzheimer's disease and dementias of late life. The information includes...
Introduction The purpose of this guide is to provide convenient and useful information on about Alzheimer's disease and dementias of late life. The information includes selected facts, diagnostic criteria tables, descriptions of selected tests and screens, guidelines, clinical pharmacological data and references. This guide is divided into several sections: Background factsDiagnostic aids and criteria for dementia diagnosesMedications used for Alzheimer's disease and dementia Basic information on marketed treatments is provided although the treatment may not be FDA approved for this use. Approved cholinesterase inhibitors, memantine, and monoclonal antibodies are listed. No treatment is recommended or endorsed, however. This guide does not address the evidence base for the efficacy of the treatments listed. : Except for treatments above, discussions of medications for people with dementia nearly always involve off label use. For example, antidepressants and antipsychotics are indicated in the FDA-approved prescribing information for major depression and schizophrenia, and not for depressive symptoms or the delusions or hallucinations occurring within the context of dementia with two exceptions. In these instances, the doses listed are for reference only and should not be considered as recommendations or appropriate use. Physicians should consult the product package labeling for any drug mentioned.
Topics: Humans; Alzheimer Disease; Antipsychotic Agents; Depressive Disorder, Major; Hallucinations; Memantine
PubMed: 37489152
DOI: No ID Found -
Alzheimer's & Dementia : the Journal of... Apr 2020This clinical trial evaluates the efficacy and safety of a 6-week course of daily neuroAD™ therapy. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
INTRODUCTION
This clinical trial evaluates the efficacy and safety of a 6-week course of daily neuroAD™ therapy.
METHODS
131 subjects between 60 and 90 years old, unmedicated for Alzheimer's disease (AD), or on stable doses of an acetylcholinesterase inhibitor and/or memantine, with Mini-Mental State Examination scores between 18 and 26, clinical dementia rating scale scores of 1 or 2, enrolled for a prospective, randomized, double-blind, sham-controlled, multicenter clinical trial. Structural brain MRIs were obtained for transcranial magnetic stimulation targeting. Baseline Alzheimer's disease assessment scale-cognitive (ADAS-Cog) and Clinical Global Impression of Change were assessed. 129 participants were randomized to active treatment plus standard of care (SOC) or sham treatments plus SOC.
RESULTS
Subjects with baseline ADAS-Cog ≤ 30 (~85% of study population) showed a statistically significant benefit favoring active over sham. Responder analysis showed 31.7% participants in the active group with ≤ -4 point improvement on ADAS-Cog versus 15.4% in the sham group.
DISCUSSION
neuroAD™ Therapy System provides a low-risk therapeutic benefit for patients with milder AD (baseline ADAS-Cog ≤30) beyond pharmacologic SOC.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Double-Blind Method; Female; Humans; Male; Memantine; Mental Status Schedule; Middle Aged; Prospective Studies; Transcranial Magnetic Stimulation
PubMed: 31879235
DOI: 10.1016/j.jalz.2019.08.197 -
Asian Journal of Psychiatry Jan 2023To integrate all evidence derived from randomized controlled trials (RCTs) of both pharmacological and nonpharmacological augmentation interventions for... (Meta-Analysis)
Meta-Analysis
Pharmacological and nonpharmacological augmentation treatments for clozapine-resistant schizophrenia: A systematic review and network meta-analysis with normalized entropy assessment.
OBJECTIVE
To integrate all evidence derived from randomized controlled trials (RCTs) of both pharmacological and nonpharmacological augmentation interventions for clozapine-resistant schizophrenia (CRS).
METHODS
Six major electronic databases were systematically searched for RCTs published until July 10, 2021. The primary outcome was change in overall symptoms, and the secondary outcomes were positive and negative symptoms and acceptability. We performed random-effects network meta-analysis. Normalized entropy was calculated to examine the uncertainty of treatment ranking.
RESULTS
We identified 35 RCTs (1472 patients with 23 active augmentation treatments) with a mean daily clozapine dose of 440.80 (91.27) mg for 1168.22 (710.28) days. Network meta-analysis of overall symptoms (reported as standardized mean difference; 95 % confidence interval) with consistent results indicated that mirtazapine (-4.41; -5.61, -3.21), electroconvulsive therapy (ECT) (-4.32; -5.43, -3.21), and memantine (-2.02; -3.14, -0.91) were ranked as the best three treatments. For positive symptoms, ECT (-5.18; -5.86, -4.49) was ranked the best with less uncertainty. For negative symptoms, memantine (-3.38; -4.50, -2.26), duloxetine (-3.27; -4.25, -2.29), and mirtazapine (-1.73; -2.71, -0.74) were ranked the best three treatments with less uncertainty. All antipsychotics, N-methyl d-aspartate receptor agonists, and antiepileptics were not associated with more efficacy than placebo. Compared to placebo, only amisulpride had statistically significant lower discontinuation rate (risk ratio: 0.21; 95 % CI: 0.05, 0.93).
CONCLUSION
Add-on mirtazapine, ECT, and memantine were the most efficacious augmentation options for CRS. Data on other important outcomes such as cognitive functioning or quality of life were rarely reported, making further large-scale, well-designed RCTs necessary. (PROSPERO number, CRD42021262197.).
Topics: Humans; Clozapine; Network Meta-Analysis; Entropy; Memantine; Mirtazapine; Antipsychotic Agents; Schizophrenia
PubMed: 36470132
DOI: 10.1016/j.ajp.2022.103375