NMDAR antagonists suppress tumor progression by regulating tumor-associated macrophages.

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.

Geographic Variation of Antidementia and Antipsychotic Medication Use Among US Nursing Home Residents With Dementia.

BACKGROUND: Several antidementia medications have been approved for symptomatic treatment of cognitive and functional impairment due to Alzheimer disease. Antipsychotics are often prescribed off-label for behavioral symptoms. OBJECTIVE: The aim of this study was to describe the basis for regional variation in antidementia and antipsychotic medication use. SETTING: US nursing homes (n=9735), hospital referral regions (HRR; n=289). SUBJECTS: Long-stay residents with dementia (n=273,004). METHODS: Using 2018 Minimum Data Set 3.0 linked to Medicare data, facility information, and Dartmouth Atlas files, we calculated prevalence of use and separate multilevel logistic models [outcomes: memantine, cholinesterase inhibitor (ChEI), antipsychotic use] estimated adjusted odds ratios (aOR) and 95% CIs for resident, facility, and HRR characteristics. We then fit a series of cross-classified multilevel logistic models to estimate the proportional change in cluster variance (PCV). RESULTS: Overall, 20.9% used antipsychotics, 16.1% used memantine, and 23.3% used ChEIs. For antipsychotics, facility factors [eg, use of physical restraints (aOR: 1.08; 95% CI: 1.05-1.11) or poor staffing ratings (aOR: 1.10; 95% CI: 1.06-1.14)] were associated with more antipsychotic use. Nursing homes in HRRs with the highest health care utilization had greater antidementia drug use (aOR memantine: 1.68; 95% CI: 1.44-1.96). Resident/facility factors accounted for much regional variation in antipsychotics (PCV STATE : 27.80%; PCV HRR : 39.54%). For antidementia medications, HRR-level factors accounted for most regional variation (memantine PCV STATE : 37.44%; ChEI PCV STATE : 39.02%). CONCLUSION: Regional variations exist in antipsychotic and antidementia medication use among nursing home residents with dementia suggesting the need for evidence-based protocols to guide the use of these medications.

Memantine Improves Memory and Neurochemical Damage in a Model of Maple Syrup Urine Disease.

Maple Syrup Urine Disease (MSUD) is a metabolic disease characterized by the accumulation of branched-chain amino acids (BCAA) in different tissues due to a deficit in the branched-chain alpha-ketoacid dehydrogenase complex. The most common symptoms are poor feeding, psychomotor delay, and neurological damage. However, dietary therapy is not effective. Studies have demonstrated that memantine improves neurological damage in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Therefore, we hypothesize that memantine, an NMDA receptor antagonist can ameliorate the effects elicited by BCAA in an MSUD animal model. For this, we organized the rats into four groups: control group (1), MSUD group (2), memantine group (3), and MSUD + memantine group (4). Animals were exposed to the MSUD model by the administration of BCAA (15.8 µL/g) (groups 2 and 4) or saline solution (0.9%) (groups 1 and 3) and treated with water or memantine (5 mg/kg) (groups 3 and 4). Our results showed that BCAA administration induced memory alterations, and changes in the levels of acetylcholine in the cerebral cortex. Furthermore, induction of oxidative damage and alterations in antioxidant enzyme activities along with an increase in pro-inflammatory cytokines were verified in the cerebral cortex. Thus, memantine treatment prevented the alterations in memory, acetylcholinesterase activity, 2',7'-Dichlorofluorescein oxidation, thiobarbituric acid reactive substances levels, sulfhydryl content, and inflammation. These findings suggest that memantine can improve the pathomechanisms observed in the MSUD model, and may improve oxidative stress, inflammation, and behavior alterations.

Antidementia Medication Use in Nursing Home Residents.

BACKGROUND: Antidementia medication can provide symptomatic improvements in patients with Alzheimer's disease, but there is a lack of consensus guidance on when to start and stop treatment in the nursing home setting. METHODS: We describe utilization patterns of cholinesterase inhibitors (ChEI) and memantine for 3,50,197 newly admitted NH residents with dementia between 2011 and 2018. RESULTS: Overall, pre-admission use of antidementia medications declined from 2011 to 2018 (ChEIs: 44.5% to 36.9%; memantine: 27.4% to 23.2%). Older age, use of a feeding tube, and greater functional dependency were associated with lower odds of ChEI initiation. Coronary artery disease, parenteral nutrition, severe aggressive behaviors, severe cognitive impairment, and high functional dependency were associated with discontinuation of ChEIs. Comparison of clinical factors related to anti-dementia drug treatment changes from pre to post NH admission in 2011 and 2018 revealed a change toward lower likelihood of initiation of treatment among residents with more functional dependency and those with indicators of more complex illness as well as a change toward higher likelihood of discontinuation in residents having 2 or more hospital stays. CONCLUSIONS: These prescribing trends highlight the need for additional research on the effects of initiating and discontinuing antidementia medications in the NH to provide clear guidance for clinicians when making treatment decisions for individual residents.

Randomized placebo-controlled crossover trial of memantine in children with epileptic encephalopathy.

Memantine is an N-methyl-D-aspartate receptor antagonist, approved for dementia treatment. There is limited evidence of memantine showing benefit for paediatric neurodevelopmental phenotypes, but no randomized placebo-controlled trials in children with developmental and epileptic encephalopathy. In this randomized double-blind placebo-controlled crossover trial (Trial registration: https://clinicaltrials.gov/ct2/show/NCT03779672), patients with developmental and epileptic encephalopathy received memantine and placebo, each for a 6-week period separated by a 2-week washout phase. Electroencephalography, seizure diary, patient caregivers' global impression, serum inflammatory markers and neuropsychological evaluation were performed at baseline and after each treatment phase. The primary outcome measure was classification as a 'responder', defined as ≥2 of: >50% seizure frequency reduction, electroencephalography improvement, caregiver clinical impression improvement or clear neuropsychological testing improvement. Thirty-one patients (13 females) enrolled. Two patients withdrew prior to initiating medication and two (twins) had to be removed from analysis. Of the remaining 27 patients, nine (33%) were classified as responders to memantine versus two (7%) in the placebo group (P < 0.02). Electroencephalography improvement was seen in eight patients on memantine compared to two on placebo (P < 0.04). Seizure improvement was observed in eight patients on memantine and two on placebo (P < 0.04). Caregivers reported overall clinical improvement in 10 patients on memantine compared to seven on placebo (not significant). Statistical analysis of neuropsychological evaluation suggested improvements in symptoms of attention-deficit hyperactivity disorder and autism. Memantine is a safe and effective treatment for children with developmental and epileptic encephalopathy, having the potential to improve both seizure control and cognitive function.

Mechanism of NMDA receptor channel block by MK-801 and memantine.

The NMDA (N-methyl-D-aspartate) receptor transduces the binding of glutamate and glycine, coupling it to the opening of a calcium-permeable ion channel 1 . Owing to the lack of high-resolution structural studies of the NMDA receptor, the mechanism by which ion-channel blockers occlude ion permeation is not well understood. Here we show that removal of the amino-terminal domains from the GluN1-GluN2B NMDA receptor yields a functional receptor and crystals with good diffraction properties, allowing us to map the binding site of the NMDA receptor blocker, MK-801. This crystal structure, together with long-timescale molecular dynamics simulations, shows how MK-801 and memantine (a drug approved for the treatment of Alzheimer's disease) bind within the vestibule of the ion channel, promote closure of the ion channel gate and lodge between the M3-helix-bundle crossing and the M2-pore loops, physically blocking ion permeation.

Memantine versus Ginkgo biloba Extract: A Comparative Study on Cognitive Dysfunction Treatment in a Novel Rat Model.

Extracellular senile plaques and intraneuronal neurofibrillary tangles are two devastating brain proteinopathies that are indicative of Alzheimer's disease, the most prevalent type of dementia. Currently, no effective medications are available to stop or reverse Alzheimer's disease. Ginkgo biloba extract, commonly referred to as EGb 761, is a natural product made from the leaves of the G. biloba tree. It has long been demonstrated to have therapeutic benefits in Alzheimer's disease. The current study assessed the beneficial effects of EGb 761 against Alzheimer's disease in comparison with memantine, a standard treatment for Alzheimer's disease. The scopolamine-heavy metals mixture rat Alzheimer's disease model is a newly created model to study the effects of EGb 761 oral therapy on cognitive performance and other Alzheimer's disease-like changes over a 28-day experimental period. This new Alzheimer's disease model provides better criteria for Alzheimer's disease hallmarks than the conventional scopolamine model. The EGb 761 reversed memory and learning deficits induced by the scopolamine-heavy metals mixture. These outcomes were linked to a more pronounced inhibitory effect on acetylcholinesterase, caspase-3, hippocampal amyloid-beta protein (Aß1 - 42), phosphorylated tau protein counts, and proinflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) compared to the memantine-treated group. Furthermore, EGb 761 treatment considerably reduced lipid peroxidation (malondialdehyde) and improved reduced glutathione levels compared to memantine. Our results suggest EGb 761's potential in treating central nervous system disorders. It's a promising candidate for future Alzheimer's disease therapeutic exploration. This study also highlights the need for future research to focus on the positive benefits of herbal medicines.

Case report: a unique presentation of memantine overdose causing echolalia and hypertension.

BACKGROUND: Since 2003 when memantine was first approved for use in the management of moderate-severe Alzheimer's dementia, its use has become more widespread and is being explored in other diseases like neuropathic pain, epilepsy, and mood disorders. Our case uniquely highlights two important adverse effects in a patient who overdosed on memantine. One is hypertension, which is easy to overlook as a medication side effect. The other is echolalia which is the repetition of words and phrases spoken by another person. It is commonly seen in children with autism spectrum disorder and has been reported in older adults with head injuries, delirium, and neurocognitive disorders. The aim of this patient story is to highlight the importance of medication reconciliation with caregivers and knowledge of adverse drug reactions in patient management. This case report has been presented previously in the form of an abstract at the American Geriatrics Society Presidential poster session in May 2023. CASE PRESENTATION: Our patient is an 86-year-old man with mild dementia and hypertension, who was brought to the emergency department (ED) due to abrupt onset of altered mental status and auditory hallucinations. Investigations including blood work, CT head and an electroencephalogram (EEG) did not reveal an etiology for this change in his condition. Due to elevated blood pressure on presentation, a nicardipine drip was started, and he was given IV midazolam to assist with obtaining imaging. While reviewing medications with his daughter, it was noted that sixty memantine pills were missing from the bottle. Poison control was contacted and they confirmed association of these features with memantine. With supportive care, his symptoms resolved in less than 100 h, consistent with the half-life of memantine. Notably, our patient was started on Memantine one month prior to this presentation. CONCLUSIONS: Hypertensive urgency and echolalia were the most striking symptoms of our patient's presentation. Though hypertension is a known sign of memantine overdose, it can easily be contributed to medication non-compliance in patients with dementia, being treated for hypertension. According to our literature review, this the first case of memantine overdose presenting with echolalia, a sign that is not commonly associated with adverse reactions to medications. This highlights the importance of an early medication review, especially with caregivers of people with dementia.

Integrative Pharmacology in the Treatment of Substance Use Disorders.

The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years to develop novel pharmacotherapies to treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy has been shown to be superior to no treatment at all for most substance classes. However, many randomized controlled trials (RCTs) have revealed that monotherapy leads to poorer outcomes when compared with combination treatment in all specialties of medicine. The results of RCTs suggest that monotherapy frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, and receptors are involved in the pathophysiology of SUDs. As such, research is urgently needed to determine how various neurobiological mechanisms can be targeted by novel combination treatments to create increasingly specific yet exceedingly comprehensive approaches to SUD treatment. This article aims to review the neurobiology that integrates many pathophysiologic mechanisms and discuss integrative pharmacology developments that may ultimately improve clinical outcomes for patients with SUDs. Many neurobiological mechanisms are known to be involved in SUDs including dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), and kynurenic acid (KYNA) mechanisms. Emerging evidence indicates that KYNA, a tryptophan metabolite, modulates all these major pathophysiologic mechanisms. Therefore, achieving KYNA homeostasis by harmonizing integrative pathophysiology and pharmacology could prove to be a better therapeutic approach for SUDs. We propose KYNA-NMDA-α7nAChRcentric pathophysiology, the "conductor of the orchestra," as a novel approach to treat many SUDs concurrently. KYNA-NMDA-α7nAChR pathophysiology may be the "command center" of neuropsychiatry. To date, extant RCTs have shown equivocal findings across comparison conditions, possibly because investigators targeted single pathophysiologic mechanisms, hit wrong targets in underlying pathophysiologic mechanisms, and tested inadequate monotherapy treatment. We provide examples of potential combination treatments that simultaneously target multiple pathophysiologic mechanisms in addition to KYNA. Kynurenine pathway metabolism demonstrates the greatest potential as a target for neuropsychiatric diseases. The investigational medications with the most evidence include memantine, galantamine, and N-acetylcysteine. Future RCTs are warranted with novel combination treatments for SUDs. Multicenter RCTs with integrative pharmacology offer a promising, potentially fruitful avenue to develop novel therapeutics for the treatment of SUDs.

Locally Synthetized 17-ß-Estradiol Reverses Amyloid-ß-42-Induced Hippocampal Long-Term Potentiation Deficits.

Amyloid beta 1-42 (Aß42) aggregates acutely impair hippocampal long-term potentiation (LTP) of synaptic transmission, and 17ß-estradiol is crucial for hippocampal LTP. We tested whether boosting the synthesis of neural-derived 17ß-estradiol (nE2) saves hippocampal LTP by the neurotoxic action of Aß42. Electrophysiological recordings were performed to measure dentate gyrus (DG) LTP in rat hippocampal slices. Using a pharmacological approach, we tested the ability of nE2 to counteract the LTP impairment caused by acute exposure to soluble Aß42 aggregates. nE2 was found to be required for LTP in DG under physiological conditions. Blockade of steroid 5α-reductase with finasteride, by increasing nE2 synthesis from testosterone (T), completely recovered LTP in slices treated with soluble Aß42 aggregates. Modulation of the glutamate N-methyl-D aspartate receptor (NMDAR) by memantine effectively rescued the LTP deficit observed in slices exposed to Aß42, and memantine prevented LTP reduction observed under the blocking of nE2 synthesis. nE2 is able to counteract Aß42-induced synaptic dysfunction. This effect depends on a rapid, non-genomic mechanism of action of nE2, which may share a common pathway with glutamate NMDAR signaling.

Acquired Risk Factors that Influence Risk for Dementia and Possibly Alzheimer Disease.

Various medicinal agents aimed at improving Alzheimer disease (AD) include cholinesterase inhibitors, memantine, aducanumab, and antioxidants. These medications are typically prescribed once AD is diagnosed in the clinical setting in order to slow progression. Though initiating treatment after being diagnosed with AD is important, significance should be placed on recognizing known acquired risk factors in order to potentially decrease the likelihood of developing dementia and perhaps specifically AD. This article summarizes the acquired factors that influence risk for dementia.

MBD5 regulates NMDA receptor expression and seizures by inhibiting Stat1 transcription.

Epilepsy is considered to result from an imbalance between excitation and inhibition of the central nervous system. Pathogenic mutations in the methyl-CpG binding domain protein 5 gene (MBD5) are known to cause epilepsy. However, the function and mechanism of MBD5 in epilepsy remain elusive. Here, we found that MBD5 was mainly localized in the pyramidal cells and granular cells of mouse hippocampus, and its expression was increased in the brain tissues of mouse models of epilepsy. Exogenous overexpression of MBD5 inhibited the transcription of the signal transducer and activator of transcription 1 gene (Stat1), resulting in increased expression of N-methyl-d-aspartate receptor (NMDAR) subunit 1 (GluN1), 2A (GluN2A) and 2B (GluN2B), leading to aggravation of the epileptic behaviour phenotype in mice. The epileptic behavioural phenotype was alleviated by overexpression of STAT1 which reduced the expression of NMDARs, and by the NMDAR antagonist memantine. These results indicate that MBD5 accumulation affects seizures through STAT1-mediated inhibition of NMDAR expression in mice. Collectively, our findings suggest that the MBD5-STAT1-NMDAR pathway may be a new pathway that regulates the epileptic behavioural phenotype and may represent a new treatment target.

Clinical Recommendations for Augmentation Agents in Obsessive-Compulsive Disorder Partially Responsive to Serotonin Reuptake Inhibitors.

BACKGROUND: Obsessive-compulsive disorder (OCD) affects 2% to 3% of adults worldwide. Although serotonin reuptake inhibitors (SRIs) reliably demonstrate efficacy for this condition, 40% to 60% of patients only achieve partial recovery. The purpose of this systematic review was to assess the efficacy of other agents that may be used as augmentation agents for patients who are partial responders to SRI monotherapy. METHODS: Using PRISMA-P guidelines, PubMed and Embase were searched using the randomized controlled trial (RCT) filter and the key word "obsessive-compulsive disorder." To be considered for analysis, a potential augmentation agent needed to have at least 2 RCTs. This review specifically analyzes the effect of each augmentation agent on OCD symptoms as measured by the Yale-Brown Obsessive-Compulsive Scale. RESULTS: The augmentation agents analyzed in this review are d -cycloserine (2 RCTs), memantine (4 RCTs), N -acetylcysteine (5 RCTs), lamotrigine (2 RCTs), topiramate (3 RCTs), riluzole (2 RCTs), ondansetron (2 RCTs), celecoxib (2 RCTs), aripiprazole (5 RCTs), risperidone (7 RCTs), quetiapine (9 RCTs), and olanzapine (3 RCTs). IMPLICATIONS: The augmentation agents most supported by this review for OCD that is only a partial response to SRI monotherapy are lamotrigine, memantine, and aripiprazole. If an antipsychotic must be used and aripiprazole is not tolerated, risperidone may be considered as an alternative. Unlike the SRI class effect for OCD symptom reduction, augmentation agents demonstrate considerable intraclass variability.

GRIN1 variants associated with neurodevelopmental disorders reveal channel gating pathomechanisms.

OBJECTIVE: N-methyl-d-aspartate (NMDA) receptors are expressed at synaptic sites, where they mediate fast excitatory neurotransmission. NMDA receptors are critical to brain development and cognitive function. Natural variants to the GRIN1 gene, which encodes the obligatory GluN1 subunit of the NMDA receptor, are associated with severe neurological disorders that include epilepsy, intellectual disability, and developmental delay. Here, we investigated the pathogenicity of three missense variants to the GRIN1 gene, p. Ile148Val (GluN1-3b[I481V]), p.Ala666Ser (GluN1-3b[A666S]), and p.Tyr668His (GluN1-3b[Y668H]). METHODS: Wild-type and variant-containing NMDA receptors were expressed in HEK293 cells and primary hippocampal neurons. Patch-clamp electrophysiology and pharmacology were used to profile the functional properties of the receptors. Receptor surface expression was evaluated using fluorescently tagged receptors and microscopy. RESULTS: Our data demonstrate that the GluN1(I481V) variant is inhibited by the open pore blockers ketamine and memantine with reduce potency but otherwise has little effect on receptor function. By contrast, the other two variants exhibit gain-of-function molecular phenotypes. Glycine sensitivity was enhanced in receptors containing the GluN1(A666S) variant and the potency of pore block by memantine and ketamine was reduced, whereas that for MK-801 was increased. The most pronounced functional deficits, however, were found in receptors containing the GluN1(Y668H) variant. GluN1(Y668H)/2A receptors showed impaired surface expression, were more sensitive to glycine and glutamate by an order of magnitude, and exhibited impaired block by extracellular magnesium ions, memantine, ketamine, and MK-801. These variant receptors were also activated by either glutamate or glycine alone. Single-receptor recordings revealed that this receptor variant opened to several conductance levels and activated more frequently than wild-type GluN1/2A receptors. SIGNIFICANCE: Our study reveals a critical functional locus of the receptor (GluN1[Y668]) that couples receptor gating to ion channel conductance, which when mutated may be associated with neurological disorder.

Minocycline Protects Against Lipopolysaccharide-Induced Cognitive Impairment and Oxidative Stress: Possible Role of the CREB-BDNF Signaling Pathway.

The oxidative stress-induced dysregulation of the cyclic AMP response element-binding protein- brain-derived neurotrophic factor (CREB-BDNF) cascade has been linked to cognitive impairment in several studies. This study aimed to investigate the effect of minocycline on the levels of oxidative stress markers, CREB, and BDNF in lipopolysaccharide (LPS)-induced cognitive impairment. Fifty adult male Sprague Dawley rats were divided randomly into five groups. Group 1 was an untreated control group. Groups 2, 3, 4 and 5 were treated concurrently with LPS (5 mg/kg, i.p) once on day 5 and normal saline (0.7 ml/rat, i.p) or minocycline (25 and 50 mg/kg, i.p) or memantine (10 mg/kg, i.p) once daily from day 1 until day 14, respectively. From day 15 to day 22 of the experiment, Morris Water Maze (MWM) was used to evaluate learning and reference memory in rats. The levels of protein carbonyl (PCO), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) were determined by enzyme-linked immunosorbent assay (ELISA). CREB and BDNF expression and density were measured by immunohistochemistry and western blot analysis, respectively. LPS administration significantly increased escape latency to the hidden platform with decreased travelled distance, swimming speed, target crossings and time spent in the target quadrant. Besides, the hippocampal tissue of LPS rats showed increased levels of PCO and MDA, decreased levels of CAT and SOD, and reduced expression and density of BDNF and CREB. Treatment with minocycline reversed these effects in a dose-dependent manner, comparable to the effects of memantine. Both doses of minocycline treatment protect against LPS-induced cognitive impairment by reducing oxidative stress and upregulating the CREB-BDNF signalling pathway in the rat hippocampus.

Simultaneous Intranasal Codelivery of Donepezil and Memantine in a Nanocolloidal Carrier: Optimization, Pharmacokinetics, and Pharmacodynamics Studies.

This work focuses on developing nanoemulsions using a low-energy emulsification method for the codelivery of donepezil and memantine in one dosage form intended to be administered via the intranasal route for enhanced brain delivery. The nanoemulsion formulation was prepared using a low emulsification technique and characterized using various microscopy and nasal ciliotoxicity studies. The safe nanoemulsion was intended for preclinical pharmacokinetics with brain distribution and pharmacodynamics in a scopolamine-induced murine model. The formulated nanoemulsion was 16 nm in size, with a zeta potential of -7.22 mV, and exhibited a spherical shape. The brain concentration of IN-administered NE for DPZ and MEM was ∼678 and 249 ng/mL after 15 min. This concentration is more than 2 times higher in amount when compared with NE administered via PO, free drug solution administered via IN and PO route both. However, the plasma concentration of IN-administered NE for DPZ and MEM was ∼3 and 28 ng/mL after 15 min. In pharmacodynamic studies, the efficacy of NE administered via the IN route was higher when compared with other groups in neurobehavioral, biochemical estimation, and gene expression studies. The results suggest that the IN route can be explored in the future for the delivery of actives via nanocolloidal carriers in the brain for neurological disorders and can serve as promising alternatives for conventional dosage forms and routes.

Prevalence of Chronic Pain Among People with Dementia: A Nationwide Study Using French Administrative Data.

OBJECTIVE: Alzheimer's disease or Related Dementia (ADRD) is known to disturb pain perception and reduce the ability to report it, resulting in underestimation by practitioners and sub-optimal medical management. The aim of this study was to estimate the prevalence of all types of CP among people with ADRD. DESIGN: Nationwide cross-sectional study. SETTINGS: French community-dwelling and nursing home residents. PARTICIPANTS: People with ADRD, >40 years old, treated with cholinesterase inhibitors or memantine, or with a diagnosis/long-term illness of ADRD and matched with a comparison sample. SETTINGS: French community-dwelling and nursing home residents. PARTICIPANTS: People with ADRD, >40 years old, treated with cognitive stimulants (cholinesterase inhibitors and memantine) or with a diagnosis/long-term illness of ADRD and matched with a comparison sample (non-ADRD). MEASUREMENTS: The capture-recapture method was performed to provide estimates of the prevalence of CP. People treated with analgesic drugs for ≥6 months consecutively or with a medical diagnosis of CP (ICD-10 codes) or referred to a pain center were considered as having CP. RESULTS: A total of 48,288 individuals were included, of which 16,096 had ADRD and 32,192 without ADRD. The estimated prevalence of CP in people with ADRD was from 57.7% [52.9;63.3] to 57.9%[53.0;63.9], and slightly higher than the non-ADRD sample (from 49.9%[47.0;53.2] to 50.4%[47.3;53.9], p <0.001). CONCLUSIONS: The prevalence of CP among people living with ADRD was at least the same as or better than individuals without ADRD. This result should alert practitioners' attention to the need for effective pain assessment and management in this population who has difficulties to express and feel pain.

Pharmacological augmentation of serotonin reuptake inhibitors in patients with obsessive-compulsive disorder: A network meta-analysis.

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.

Effects of Pharmacological Treatments in Alzheimer's Disease: Permutation Entropy-Based EEG Complexity Study.

Alzheimer's disease (AD) is a neurodegenerative brain disease affecting cognitive and physical functioning. The currently available pharmacological treatments for AD mainly contain cholinesterase inhibitors (AChE-I) and N-methyl-D-aspartic acid (NMDA) receptor antagonists (i.e., memantine). Because brain signals have complex nonlinear dynamics, there has been an increase in interest in researching complexity changes in the time series of brain signals in individuals with AD. In this study, we explore the electroencephalographic (EEG) complexity for making better observation of pharmacological therapy-based treatment effects on AD patients using the permutation entropy (PE) method. We examined EEG sub-band (delta, theta, alpha, beta, and gamma) complexity in de-novo, monotherapy (AChE-I), dual therapy (AChE-I and memantine) receiving AD participants compared with healthy elderly controls. We showed that each frequency band depicts its own complexity profile, which is regionally altered between groups. These alterations were also found to be associated with global cognitive scores. Overall, our findings indicate that entropy measures could be useful to show medication effects in AD.

Esmethadone-HCl (REL-1017): a promising rapid antidepressant.

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.