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Neurocognitive Outcomes from Memantine: A Pilot, Double-Blind, Placebo-Controlled Trial in Children with Autism Spectrum Disorder.
Soorya, LV, Fogg, L, Ocampo, E, Printen, M, Youngkin, S, Halpern, D, Kolevzon, A, Lee, S, Grodberg, D, Anagnostou, E
Journal of child and adolescent psychopharmacology. 2021;(7):475-484
Abstract
Objective: Studies interrogating therapeutics which alter the excitation-inhibition balance in the treatment of autism spectrum disorder (ASD) have reported mixed results on social and behavioral outcomes. Methods: The aim of this randomized, double-blind placebo-controlled pilot trial was to evaluate neurocognitive effects of memantine over a 24-week trial. Twenty-three children ages 6-12 years old with ASD were randomized to memantine or placebo. Primary outcomes included measures of apraxia and expressive language with evaluations at midpoint (week 12) and endpoint (week 24). Secondary outcomes included memory and adaptive behavior measures. Exploratory outcomes included changes in overall cognitive functioning and behavior (e.g., Aberrant Behavior Checklist). Results: Results suggest that memantine was well-tolerated. Dropout rates were high across groups with only 14 participants completing the 6-month trial. Memantine was not associated with improvements in apraxia and expressive language. Treatment with memantine was associated with improvements in verbal recognition memory as measured by the Narrative Memory-Recognition (NEPSY-II) (F = 5.05, p = .03). In addition, exploratory analyses of changes in Intelligence quotient (IQ) suggest improvements on verbal IQ (d = 1.8). Conclusions: Results suggest future studies of memantine in ASD may benefit from shifting treatment targets from social and behavioral outcomes to exploration of effects of memantine on cognition, potentially as an adjunct to learning and educational interventions. ClinicalTrials.gov: NCT01372449.
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Using Biomarkers to Predict Memantine Effects in Alzheimer's Disease: A Proposal and Proof-Of-Concept Demonstration.
Swerdlow, NR, Kotz, JE, Joshi, YB, Talledo, J, Sprock, J, Molina, JL, Huisa, B, Huege, SF, Romero, JA, Walsh, MJ, et al
Journal of Alzheimer's disease : JAD. 2021;(4):1431-1438
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Abstract
Memantine's benefits in Alzheimer's disease (AD) are modest and heterogeneous. We tested the feasibility of using sensitivity to acute memantine challenge to predict an individual's clinical response. Eight participants completed a double-blind challenge study of memantine (placebo versus 20 mg) effects on autonomic, subjective, cognitive, and neurophysiological measures, followed by a 24-week unblinded active-dose therapeutic trial (10 mg bid). Study participation was well tolerated. Subgroups based on memantine sensitivity on specific laboratory measures differed in their clinical response to memantine, some by large effect sizes. It appears feasible to use biomarkers to predict clinical sensitivity to memantine.
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Application of Real-World Data and the REWARD Framework to Detect Unknown Benefits of Memantine and Identify Potential Disease Targets for New NMDA Receptor Antagonists.
Kern, DM, Cepeda, MS, Flores, CM, Wittenberg, GM
CNS drugs. 2021;(2):243-251
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BACKGROUND Observational data may inform novel drug development programs by identifying previously unappreciated, clinical benefits of existing drugs. Several preclinical and clinical studies have suggested emergent therapeutic utility of drugs acting on the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors, including the antidementia drug memantine. METHODS Using a self-controlled cohort study design, the association of exposure to the NMDA receptor antagonist memantine with the incidence of all observed disease outcomes in four US administrative claims databases, spanning from January 2000 through January 2019, was assessed. The databases used in this study were the IBM MarketScan® Commercial Database (CCAE), the IBM MarketScan® Multi-State Medicaid Database (MDCD), the IBM MarketScan® Medicare Supplemental Database (MDCR), and the Optum© De-Identified Clinformatics® Data Mart Database. Outcomes were defined according to the unique Systematized Nomenclature of Medicine-Clinical Terms (SNOMED CT) classification system codes and required a diagnosis on two or more distinct dates. Of 20,953 outcomes assessed, only those for which memantine was associated with a ≥ 50% reduction in risk in two or more databases were included. A meta-analysis with random effects was used to pool data across the databases. RESULTS Overall, 312,336 patients were exposed to memantine during the study. After removing conditions related to dementia and memory loss, 60 outcomes met the threshold criteria. Results fell into five disease categories: mental disorders, substance use disorders, pain, gastrointestinal and colon disorders, and demyelinating disease. The bulk of findings fell into the first two groups, with 28 outcomes related to mental disorders and 24 related to substance use disorders. CONCLUSION The present results confirm that NMDA receptor antagonism may have broader therapeutic utility than previously recognized. Further observational and clinical research may be warranted to explore the therapeutic benefit of NMDA antagonists for the outcomes found in this study.
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Donepezil plus memantine versus donepezil alone for treatment of concomitant Alzheimer's disease and chronic obstructive pulmonary disease: a retrospective observational study.
Cao, Y, Qian, L, Yu, W, Li, T, Mao, S, Han, G
The Journal of international medical research. 2020;(2):300060520902895
Abstract
OBJECTIVE To assess the clinical outcomes of donepezil plus memantine (DM) and donepezil (DO) alone in Asian patients with a concomitant diagnosis of moderate-to-severe Alzheimer’s disease and mild-to-moderate chronic obstructive pulmonary disease (AD-COPD). METHODS We conducted a retrospective analysis of patients with AD-COPD who received either DM or DO for 6 months, or until the occurrence of unacceptable adverse events or disease progression, between June 2012 and May 2016. The primary endpoint was the score on the Standardized Mini-Mental State Examination (SMMSE). Secondary endpoints were scores on the caregiver-rated Bristol Activities of Daily Living Scale, Neuropsychiatric Inventory, Dementia Quality of Life (DEMQOL)-Proxy, and General Health Questionnaire 12. RESULTS In total, 154 eligible patients received DM, whereas 156 received DO. Compared with patients who received DO, patients who received DM had significantly higher mean scores on the SMMSE by 2.1 points (95% confidence interval, 1.3–2.5). Significant between-group heterogeneity was not detected in outcomes over time. The benefits of treatment with DM were greater than those of treatment with DO, in terms of the primary endpoint. Significant differences were also detected in terms of secondary endpoints. CONCLUSION DM is more effective than DO alone for Asian patients with AD-COPD.
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Gabapentin and Memantine for Treatment of Acquired Pendular Nystagmus: Effects on Visual Outcomes.
Nerrant, E, Abouaf, L, Pollet-Villard, F, Vie, AL, Vukusic, S, Berthiller, J, Colombet, B, Vighetto, A, Tilikete, C
Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society. 2020;(2):198-206
Abstract
BACKGROUND The most common causes of acquired pendular nystagmus (APN) are multiple sclerosis (MS) and oculopalatal tremor (OPT), both of which result in poor visual quality of life. The objective of our study was to evaluate the effects of memantine and gabapentin treatments on visual function. We also sought to correlate visual outcomes with ocular motor measures and to describe the side effects of our treatments. METHODS This study was single-center cross-over trial. A total of 16 patients with chronic pendular nystagmus, 10 with MS and 6 with OPT were enrolled. Visual acuity (in logarithm of the minimum angle of resolution [LogMAR]), oscillopsia amplitude and direction, eye movement recordings, and visual function questionnaires (25-Item National Eye Institute Visual Functioning Questionnaire [NEI-VFQ-25]) were performed before and during the treatments (gabapentin: 300 mg 4 times a day and memantine: 10 mg 4 times a day). RESULTS A total of 29 eyes with nystagmus were evaluated. Median near monocular visual acuity improved in both treatment arms, by 0.18 LogMAR on memantine and 0.12 LogMAR on gabapentin. Distance oscillopsia improved on memantine and on gabapentin. Median near oscillopsia did not significantly change on memantine or gabapentin. Significant improvement in ocular motor parameters was observed on both treatments. Because of side effects, 18.8% of patients discontinued memantine treatment-one of them for a serious adverse event. Only 6.7% of patients discontinued gabapentin. Baseline near oscillopsia was greater among those with higher nystagmus amplitude and velocity. CONCLUSIONS This study demonstrated that both memantine and gabapentin reduce APN, improving functional visual outcomes. Gabapentin showed a better tolerability, suggesting that this agent should be used as a first-line agent for APN. Data from our investigation emphasize the importance of visual functional outcome evaluations in clinical trials for APN.
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Galantamine-Memantine combination in the treatment of Alzheimer's disease and beyond.
Koola, MM
Psychiatry research. 2020;:113409
Abstract
Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population worldwide. Despite the major unmet clinical need, no new medications for the treatment of AD have been approved since 2003. Galantamine is an acetylcholinesterase inhibitor that is also a positive allosteric modulator at the α4β2 and α7nACh receptors. Memantine is an N-methyl-d-aspartate receptor modulator/agonist. Both galantamine and memantine are FDA-approved medications for the treatment of AD. The objective of this review is to highlight the potential of the galantamine-memantine combination to conduct randomized controlled trials (RCTs) in AD. Several studies have shown the combination to be effective. Neurodegenerative diseases involve multiple pathologies; therefore, combination treatment appears to be a rational approach. Although underutilized, the galantamine-memantine combination is the standard of care in the treatment of AD. Positive RCTs with the combination with concurrent improvement in symptoms and biomarkers may lead to FDA approval, which may lead to greater utilization of this combination in clinical practice.
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Influence of combined treatment with naltrexone and memantine on alcohol drinking behaviors: a phase II randomized crossover trial.
Krishnan-Sarin, S, O'Malley, SS, Franco, N, Cavallo, DA, Tetrault, JM, Shi, J, Gueorguieva, R, Pittman, B, Krystal, JH
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2020;(2):319-326
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Glutamate and opioid systems play important roles in alcohol drinking behaviors. We examined if combined treatment with the NMDA antagonist memantine and the opioid antagonist naltrexone, when compared with naltrexone alone, would have a greater influence on alcohol drinking behaviors. Fifty-six, non-treatment-seeking heavy drinkers, with alcohol dependence and a positive family history (FHP) of alcoholism, participated in a randomized, double-blind, crossover trial, including two 6-8 days treatment periods, separated by a 6-day washout, and 3 alcohol drinking paradigm (ADP) sessions. After the first baseline (BAS) ADP1 session, participants were randomized to receive either naltrexone (NTX; 50 mg/day) + placebo memantine, or NTX (50 mg/day) + memantine (MEM; 20 mg/day), during the first treatment period, following which they completed ADP2. After a 6-day washout, participants were crossed over to the treatment they did not receive during the first treatment period, following which they completed ADP3. During each ADP, participants received a priming drink of alcohol followed by 3 1-hour, self-administration periods during which they had ad-lib access to 12 drinks. Individually, both NTX and NTX + MEM, when compared to BAS ADP1, significantly reduced the number of drinks consumed (p's < 0.001) and craving (p's < 0.001). When comparing NTX + MEM vs. NTX on number of drinks consumed, there was a significant treatment* sequence interaction (p = 0.004). Specifically, when NTX + MEM followed NTX alone, NTX + MEM resulted in a further reduction in drinking (mean: -1.94; 95% CI: -2.6, -0.8, p = 0.0005). However, when NTX alone followed NTX + MEM, NTX alone did not lead to further reduction in drinking (mean: 0.59; 95% CI: -0.67, 1.43, p = 0.47). Similar patterns were observed for alcohol craving; specifically, a significant reduction in craving was observed when NTX + MEM followed NTX alone (p = 0.009), but craving reduction was maintained when NTX + MEM was followed by NTX alone. Neither treatment condition significantly influenced alcohol-induced stimulation or sedation. Memantine (at a dose of 20 mg/day) enhances the efficacy of naltrexone (50 mg/day) in reducing alcohol drinking and craving among FHP drinkers with beneficial effects that appear to carryover after discontinuation of memantine treatment.
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Efficacy and safety of memantine in children with autism spectrum disorder: Results from three phase 2 multicenter studies.
Hardan, AY, Hendren, RL, Aman, MG, Robb, A, Melmed, RD, Andersen, KA, Luchini, R, Rahman, R, Ali, S, Jia, XD, et al
Autism : the international journal of research and practice. 2019;(8):2096-2111
Abstract
Three phase 2 trials were conducted to assess the efficacy and long-term safety of weight-based memantine extended release (ER) treatment in children with autism spectrum disorder. MEM-MD-91, a 50-week open-label trial, identified memantine extended-release treatment responders for enrollment into MEM-MD-68, a 12-week randomized, double-blind, placebo-controlled withdrawal trial. MEM-MD-69 was an open-label extension trial in which participants from MEM-MD-68, MEM-MD-91, and open-label trial MEM-MD-67 were treated ⩽48 weeks with memantine extended release. In MEM-MD-91, 517 (59.6%) participants were confirmed Social Responsiveness Scale responders at week 12; mean Social Responsiveness Scale total raw scores improved two to three times a minimal clinically important difference of 10 points. In MEM-MD-68, there was no difference between memantine and placebo on the primary efficacy parameter, the proportion of patients with a loss of therapeutic response (defined as ⩾10-point increase from baseline in Social Responsiveness Scale total raw score). MEM-MD-69 exploratory analyses revealed mean standard deviation improvement in Social Responsiveness Scale total raw score of 32.4 (26.4) from baseline of the first lead-in study. No new safety concerns were evident. While the a priori-defined efficacy results of the double-blind trial were not achieved, the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.
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Ginkgo biloba Extract (EGb761), Cholinesterase Inhibitors, and Memantine for the Treatment of Mild-to-Moderate Alzheimer's Disease: A Network Meta-Analysis.
Thancharoen, O, Limwattananon, C, Waleekhachonloet, O, Rattanachotphanit, T, Limwattananon, P, Limpawattana, P
Drugs & aging. 2019;(5):435-452
Abstract
BACKGROUND Cholinesterase inhibitors (ChEIs) and memantine have been reported to provide modest benefits for cognition and aspects of functioning in Alzheimer's disease (AD). Ginkgo biloba extract (EGb761), a phytomedicine, is widely used and expected to be well-tolerated. A few trials have compared EGb761 with ChEIs, and the results were inconclusive. OBJECTIVE A network meta-analysis was conducted to evaluate the therapeutic benefits and tolerability of EGb761, three ChEIs (donepezil, galantamine, and rivastigmine), and memantine in mild-to-moderate AD patients. METHODS Electronic databases were searched through 30 June 2017. We included randomized double-blinded trials with a minimum treatment duration of 22 weeks for EGb761 240 mg/day and 12 weeks for ChEIs or memantine. The study patients included AD or probable AD patients without other types of dementia or neurological disorders. Cognition, function, and behavior symptoms were compared between treatments using the standardized mean difference (SMD). Clinical global impression, treatment discontinuation, and adverse events were compared between treatments using the relative risk (RR). Statistical pooling of the individual trial results was conducted using a frequentist approach. The probability of being the best for a treatment was estimated using surface under the cumulative ranking. RESULTS EGb761 and memantine showed no therapeutic benefits in all study outcomes. For cognition, all ChEIs were significantly better than placebo (SMD from - 0.52 to - 0.26), and galantamine was better than rivastigmine in the oral and patch forms, EGb761, and memantine (SMD [95% confidence interval (CI)]: - 0.22 [- 0.40 to - 0.05]; - 0.26 [- 0.45 to - 0.07]; - 0.34 [- 0.56 to - 0.12]; and - 0.42 [- 0.71 to - 0.13], respectively). Compared to placebo, galantamine, the rivastigmine patch, and oral rivastigmine provided modest functional benefits (SMD, from 0.21 to 0.24), and galantamine provided behavioral benefits (SMD [95% CI]: - 0.15 [- 0.26 to - 0.04]). All ChEIs provided a better improvement in clinical global impression than placebo (RR from 1.20 to 1.69). The global impression ratings were more improved with donepezil than with galantamine (RR [95% CI]: 1.40 [1.09-1.80]) or with EGb761 (RR [95% CI]: 1.40 [1.06-1.85]), with a 96% probability of donepezil being more effective than the other study agents. Rivastigmine in oral and patch forms, galantamine, and donepezil had a higher risk of being discontinued than placebo (RR [95% CI]: 2.14 [1.49-3.06]; 2.04 [1.30-3.20]; 1.79 [1.28-2.49]; 1.49 [1.03-2.17], respectively). Discontinuation of EGb761 was not statistically lower than that of the ChEIs, in which donepezil had the lowest probability (38%) of being discontinued. CONCLUSION EGb761 and memantine showed no treatment benefits compared to placebo and ChEIs. Galantamine provided the highest beneficial effect on cognition and behavioral symptoms. Donepezil provided a better clinical global impression and tolerability than the other ChEIs and EGb761, with a similar benefit for cognition as galantamine.
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Adjunctive memantine for major mental disorders: A systematic review and meta-analysis of randomized double-blind controlled trials.
Zheng, W, Zhu, XM, Zhang, QE, Cai, DB, Yang, XH, Zhou, YL, Ungvari, GS, Ng, CH, He, SH, Peng, XJ, et al
Schizophrenia research. 2019;:12-21
Abstract
OBJECTIVE As a non-competitive N-methyl-d-aspartate receptor antagonist, memantine has been used to treat major mental disorders including schizophrenia, bipolar disorder, and major depressive disorder (MDD). This meta-analysis systematically investigated the effectiveness and tolerability of adjunctive memantine for patients with schizophrenia, bipolar disorder, and MDD. METHODS Only randomized controlled trials (RCTs) were identified and included in the study. Data of the three disorders were separately synthesized using the RevMan 5.3 software. RESULTS Fifteen RCTs (n = 988) examining memantine (5-20 mg/day) as an adjunct treatment for schizophrenia (9 trials with 512 patients), bipolar disorder (3 trials with 319 patients), and MDD (3 trials with 157 patients) were analyzed. Memantine outperformed the comparator regarding total psychopathology with a standardized mean difference (SMD) of -0.56 [95% confidence interval (CI): -1.01, -0.11; I2 = 76%, P = 0.01] and negative symptoms with an SMD of -0.71 (95% CI: -1.09, -0.33; I2 = 74%, P = 0.0003) in schizophrenia, but no significant effects were found with regard to positive symptoms and general psychopathology in schizophrenia, or depressive and manic symptoms in bipolar disorder or depressive symptoms in MDD. Memantine outperformed the comparator in improving cognitive performance in schizophrenia with an SMD of 1.07 (95% CI: 0.53, 1.61; P < 0.0001, I2 = 29%). No group differences were found in the rates of adverse drug reactions and discontinuation due to any reason in the three major mental disorders. CONCLUSIONS Memantine as an adjunct treatment appears to have significant efficacy in improving negative symptoms in schizophrenia. The efficacy and safety of adjunctive memantine for bipolar disorder or MDD needs to be further examined. REVIEW REGISTRATION PROSPERO 42018099045.