BackgroundAlzheimer's disease (AD) remains a therapeutic challenge, and adding other agents to donepezil may offer additional benefits.ObjectiveThis network meta-analysis aimed to compare the efficacy of donepezil-based combination therapies versus donepezil monotherapy in patients with AD.MethodsWe searched PubMed, Embase, Cochrane Library and Web of Science up to October 2025 for randomized-controlled trials comparing donepezil plus another drug with donepezil alone. The primary outcomes were cognitive function [Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog)], behavioral function (Neuropsychiatric Inventory) and functional ability [Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL)]. A frequentist network meta-analysis was performed, and treatments were ranked by SUCRA (Surface under the cumulative ranking curve) values. Time-stratified analyses were also conducted.Results41 trials involving 9822 patients were included. Compared with placebo, several combinations significantly improved MMSE and ADAS-cog scores, with Don (Donepezil) + Mas (Masitinib) (97.5%, 92.9%), Don + NBP (DL-3-n-butylphthalide) (82.5%, 74.5%) and Don + DSC (Dengzhan shengmai capsule) (81.4%) ranking highest. For ADCS-ADL, Don + Mas (92.7%), Don + NBP (74.1%), and Don + DSC (77.1%) showed significant improvements. No combination was statistically superior to donepezil monotherapy for any outcome, but numerical trends favored combination therapy across all time windows. The certainty of evidence was mostly moderate to low.ConclusionsSeveral donepezil-based combination therapies, particularly those with masitinib, NBP, DSC, and memantine, are more effective than placebo in improving cognitive and functional outcomes in AD. Although direct comparisons with donepezil monotherapy did not reach statistical significance, consistent trends support the potential of add-on strategies. Longer-term trials are needed to confirm sustained benefits.

Alzheimer's disease (AD) is the leading cause of dementia worldwide, disproportionately affecting individuals over 65 years of age and imposing a rapidly escalating burden on healthcare systems and caregivers globally. For decades, management relied on symptomatic agents-cholinesterase inhibitors and memantine-that provide modest cognitive benefits without altering disease progression. The recent approvals of the anti-amyloid monoclonal antibodies lecanemab (2023) and donanemab (2024) represent a paradigm shift, offering the first therapies that modestly but significantly slow clinical decline by targeting the underlying amyloid-β pathology. However, these advances are accompanied by important safety concerns, particularly amyloid-related imaging abnormalities, substantial costs, and unresolved questions regarding long-term clinical meaningfulness and equitable access. This comprehensive review synthesizes current knowledge across the full spectrum of AD, encompassing molecular pathophysiology (amyloid cascade, tau hyperphosphorylation, and neuroinflammation), genetic architecture (familial mutations and APOE-mediated risk), evolving biomarker-based diagnostic frameworks, established symptomatic treatments, and newly approved disease-modifying agents. We further examine emerging therapeutic strategies, including tau-targeted therapies, neuroinflammation-directed approaches, multi-target and combination strategies, drug delivery innovations, and prevention trials in preclinical populations. Throughout, we critically evaluate the evidence, acknowledging controversies and limitations while identifying promising future directions. Importantly, integrating these diagnostic and genetic advances into geriatric care settings presents unique implementation challenges, as aging populations often face comorbidities, polypharmacy, and limited access to specialized diagnostic infrastructure. As AD therapeutics enter a new era, integrating pharmacological interventions with biomarker-guided patient selection, rigorous safety monitoring, and modifiable risk factor management will be essential for optimizing outcomes in aging populations.

Background: Alterations in glutamatergic homeostasis have been implicated in Alzheimer's disease, but the relationship between total hippocampal tissue glutamate and Alzheimer-like molecular alterations remains unclear. This study evaluated the early neuroprotective potential of gentisic acid (GA) and erucic acid (EA) in an intracerebroventricular streptozotocin (icv-STZ)-induced rat model of sporadic Alzheimer-like pathology. Methods: Sixty-four female Sprague-Dawley rats were randomly assigned to eight groups: control, sham, STZ, STZ + GA (100 or 200 mg/kg/day), STZ + EA (25 or 50 mg/kg/day), and STZ + memantine (10 mg/kg/day). Treatments began immediately after STZ and continued orally for 21 days. Behavioral performance was assessed by Morris water maze and passive avoidance tests. Total hippocampal tissue glutamate was quantified by LC-MS/MS. Neuronal degeneration was assessed histopathologically, whereas tau, amyloid-β, and AChE immunoreactivity and tau-, APP-, and AChE-related in situ hybridization signals were evaluated. Results: Compared with controls, STZ-treated rats exhibited poorer behavioral performance, higher total hippocampal tissue glutamate, greater neuronal degeneration, and increased molecular signals. GA and EA administration was associated with attenuation of these alterations, with generally stronger effects at higher doses. EA at 50 mg/kg/day showed the lowest mean total hippocampal tissue glutamate among treatment groups. GA at 200 mg/kg/day and EA at 50 mg/kg/day showed the most consistent preservation across behavioral, histopathological, and molecular endpoints. Conclusions: Early GA and EA administration was associated with neuroprotective effects in the icv-STZ model. Because treatment began immediately after STZ administration, the findings support early or preventive neuroprotection rather than reversal of established Alzheimer-like pathology. Total tissue glutamate measurements neither distinguish extracellular glutamate nor directly demonstrate glutamate-mediated excitotoxicity.

Formerly recognized as an opioid receptor, the sigma-1 receptor (σ1R) is a multifunctional chaperone protein that plays a crucial role in regulating neuronal signaling, neuroprotection, and synaptic plasticity. Increasing evidence highlights a tight functional association between the σ1R and the N-methyl-D-aspartate receptor (NMDAR), a central mediator of excitatory neurotransmission and calcium-dependent neuronal processes. This review summarizes the shared signaling pathways underlying σ1R and NMDAR activity, including calcium homeostasis, calcium/calmodulin-dependent protein kinases (CaMKs), protein kinase C (PKC), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) cascades, as well as transcriptional regulators such as cAMP response element-binding protein (CREB), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and B-cell lymphoma 2 (Bcl-2). Experimental data demonstrate that pharmacological agents initially characterized as NMDAR antagonists-such as ketamine, dextromethorphan, and memantine-also interact with σ1R, suggesting that their therapeutic efficacy may arise from coordinated modulation of both receptor systems. These findings collectively indicate that the σ1R is a key regulatory element enabling proper NMDAR function and that disruption of this interaction may contribute to excitatory imbalance implicated in the pathophysiology of neuropsychiatric disorders. Recognizing the σ1R-NMDAR crosstalk as an integrated signaling axis may thus inform the development of dual-target therapeutic strategies aimed at improving neuronal resilience and clinical outcomes in psychiatric and neurodegenerative diseases.

Cholestasis and hepatitis in infants occur for various reasons and require further evaluation. We present an 8-week-old term male infant with cholestasis secondary to breast milk transference of memantine. To the best of our knowledge, this is the first case associated with cholestasis and acute hepatitis with memantine transference through breast-feeding.

Patient-facing medical AI chatbots are entering clinical use faster than evidence can characterise their real-world safety. We evaluated one deployed system and introduce CARE-LLM, a proposed framework for conversation-level post-market surveillance.

Drug repurposing refers to the process of using an existing drug or drug candidate for a new treatment or medical condition for which it was not indicated before. The process of "drug repurposing" usually involves an FDA-approved entity which has undergone clinical development and have a with well-established safety and toxicity profile in patients. Several convergent studies show that repurposed drugs may present a promising strategy for the management and therapy of several human cancers. Memantine is used to combat dementia in moderate-to-severe Alzheimer's disease (AD) patients. Several convergent studies show that memantine (and its analogs) may have applications in multiple disease conditions associated with human cancers. Memantine and its related compounds have shown promise as neuroprotective agents, anti-fatigue agents and pain-relieving agents to alleviate the toxic side effects of radiation therapy and chemotherapy. Recent publications have revealed that memantine displays anti-cancer activity by exerting direct growth-suppressive activity on the primary tumor as modulating the genomic/cellular landscape of the tumor microenvironment. Currently, clinical trials are in progress, which aim to evaluate the potential applications of memantine in cancer treatment. The adamantane scaffold in memantine has proved to be a versatile tool for the discovery of synthetic memantine analogs with robust anti-cancer activity. The discovery of second-generation memantine analogs may have wider applications in combating cancer recurrence and addressing clinical challenges in the treatment of drug-resistant and metastatic cancers.

Glutamate mediated hyperexcitability related to enhanced activation of N-methyl-D-aspartate receptors (NMDARs) is involved in different pathologies, and one of them is Alzheimer's disease (AD). Despite the development of many NMDAR inhibitors over the last decades, only memantine (MEM) has reached clinical use in AD due to a successful balance of activity, kinetics and mechanisms of action. However, given that MEM has demonstrated only limited symptomatic relief to patients, there is still a need to identify novel NMDAR blockers with suitable properties. In this work, we have studied for the first time the action of recently synthesized MEM derivative fluoroethylnormemantine (FENM) on native rat NMDARs of CA1 hippocampal pyramidal neurons using whole-cell patch clamp method. FENM inhibited NMDA receptors more moderately than MEM, but still effectively, with an IC50 value of 6.6 ± 0.6 μM, while MEM had an IC50 of 0.8 ± 0.1 μM at -80 mV holding voltage. Moreover, FENM inhibited NMDARs via similar mechanisms of action to those of MEM - voltage-dependent channel block with partial trapping and rather fast kinetics - which are important for clinical effectiveness and tolerability. Faster kinetics and moderate activity, still within micromolar range, might alleviate side effects known for MEM. The obtained parameters, as well as the details of mechanisms of action, extend our view of FENM interaction with NMDARs, helping in its development as a new neuroprotective drug.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited disease-modifying treatment options. Memantine, an N-methyl-D-aspartate receptor antagonist, has been investigated in ALS, but its safety remains unclear. This study systematically assessed the safety of memantine in adults with ALS. A systematic review and meta-analysis was conducted following PRISMA 2020 guidelines, searching PubMed, Cochrane Library, Scopus, and Web of Science for randomized controlled trials of memantine in adults with ALS. Outcomes included ALSFRS-R and FVC decline, adverse neurological events, total and serious adverse events, treatment discontinuation, and all-cause mortality. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Because of heterogeneous reporting and missing variance estimates, ALSFRS-R and FVC outcomes were synthesized narratively; only safety outcomes were pooled quantitatively. Three randomized controlled trials (706 participants) met the inclusion criteria. Functional and respiratory outcomes could not be pooled because of heterogeneous reporting, and no consistent benefit was observed. Memantine showed lower headache incidence than placebo (RR 0.43; 95% CI 0.19-0.96), with no significant differences in constipation, falls, dizziness, treatment discontinuation, or all-cause mortality. Memantine showed a borderline increase in serious adverse events (RR 1.52; 95% CI 1.00-2.31) and a higher risk of total adverse events (RR 1.19; 95% CI 1.09-1.30). Memantine was associated with a small but significant increase in total adverse events and a trend toward more serious adverse events, without improving functional decline, respiratory function, or survival in ALS. Current evidence does not support its use as a disease-modifying or adjunctive therapy. Trial registration: PROSPERO CRD420261277874.

Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD). Consequently, potentially inappropriate medication (PIM) use is particularly common among older adults with AD. Psychotropic polypharmacy may increase the risk of various adverse outcomes beyond cognitive decline. Although geriatric prescribing criteria and dementia-care guidelines offer important safety recommendations, a clinically integrated framework for potentially inappropriate psychotropic medication use in older adults with AD remains insufficiently developed. This article is a narrative review rather than a systematic review or meta-analysis. The authors searched the literature in PubMed, Embase, and the Cochrane Library, focusing on studies, guidelines, consensus statements, regulatory safety warnings, and medication-safety criteria published between January 2015 and June 2026. This review specifically examines anticholinergic drugs, antipsychotics, benzodiazepines and Z-drugs, tricyclic antidepressants, and select newer antidepressants-including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazapine, trazodone, and paroxetine-guided by the 2023 American Geriatrics Society (AGS) Beers Criteria®. Current evidence indicates that these medications may contribute to cognitive decline through anticholinergic burden, sedation, and pharmacodynamic interactions with cholinesterase inhibitors, such as donepezil and memantine. However, the strength of evidence varies considerably across drug classes and study designs, ranging from randomized controlled trials to observational studies and expert consensus. This study also summarizes current nonpharmacological strategies and proposes a structured clinical medication review framework. Overall, this review highlights the importance of minimizing inappropriate psychotropic use in AD, prioritizing non-pharmacological interventions, and conducting individualized risk-benefit assessments in clinical practice.

Catatonia is often underrecognized and underdiagnosed, particularly in young children. Catatonia occurs secondary to a medical and/or psychiatric etiology. The diagnosis can be supported by validated rating scales, including the Pediatric Catatonia Rating Scale and/or response to a dose of a benzodiazepine, often lorazepam. We present the case of a 6-year-old boy with acute behavioral changes in speech, affect, awareness, and new odd behaviors, admitted to a quaternary care pediatric hospital for further assessment and work-up of symptoms consistent with catatonia. Laboratory testing was notable for previously undiagnosed Becker muscular dystrophy (BMD), although otherwise unremarkable. He received many medication treatments for catatonia, including escalating doses of lorazepam and augmentation with memantine, zolpidem, quetiapine, and ultimately clozapine, without adequate symptom improvement and with side effects including significant weight gain. Neither behavioral interventions nor empirical treatment of presumed seronegative autoimmune encephalitis with intravenous immunoglobulin and methylprednisolone conferred benefit. He ultimately received electroconvulsive therapy, with significant and relatively rapid improvement occurring over 2 weeks after a 4-month hospitalization. This case highlights the importance of the identification of catatonia to guide evidence-based treatment and the value of timely access to electroconvulsive therapy for pediatric patients. While the etiology of his catatonia remains undetermined, his diagnosis of BMD could play a role and further supports the importance of a comprehensive medical work-up.