Memantine for the Treatment of Dementia: A Review on its Current and Future Applications

Folch, Jaume; Busquets, Oriol; Ettcheto, Miren; Sánchez-López, Elena; Castro-Torres, Ruben Dario; Verdaguer, Ester; Garcia, Maria Luisa; Olloquequi, Jordi; Casadesús, Gemma; Beas-Zarate, Carlos; Pelegri, Carme; Vilaplana, Jordi; Auladell, Carme; Camins, Antoni

doi:10.3233/jad-170672

Cited by 247Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchDementia and Cognitive Impairment Research

Memantine for the Treatment of Dementia: A Review on its Current and Future Applications

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Folch, Jaume, Busquets, Oriol, Ettcheto, Miren, Sánchez-López, Elena, Castro-Torres, Ruben Dario, Verdaguer, Ester, Garcia, Maria Luisa, Olloquequi, Jordi +6 more·2018·Journal of Alzheimer s Disease

DOI 10.3233/jad-170672PMC PMC5870028

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Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered.

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Memantine showed promising anti-Alzheimer effects in preclinical experimental models, but in clinical studies it has not shown clear therapeutic efficacy in Alzheimer's disease.
“Memantine showed promising anti-Alzheimer effects in preclinical experimental models, however, in clinical studies, it has not shown clear therapeutic efficacy in AD [33].”
From Indian Medicinal Herbs and Formulations for Alzheimer’s Disease, from Traditional Knowledge to Scientific Assessment (2020) · cites this paper as [33]

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Zhu, G., Li, J., He, L., Wang, X., & Hong, X. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13061 · Cited by 118 · see citing works
The basal forebrain cholinergic system in aging and dementia. Rescuing cholinergic neurons from neurotoxic amyloid-β42 with memantine
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Neurochemical and behavioural effects of acute and chronic memantine administration in rats: Further support for NMDA as a new pharmacological target for the treatment of depression?
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Memantine in Behavioral Variant Frontotemporal Dementia: Negative Results
Vercelletto, M., Boutoleau-Bretonnière, C., Volteau, C., Puel, M., Auriacombe, S., Sarazin, M., Michel, B., Couratier, P., Thomas-Antérion, C., Verpillat, P., et al. (2011) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-101632 · Cited by 109 · see citing works
Effectiveness of the Combination of Memantine Plus Vitamin D on Cognition in Patients With Alzheimer Disease
Annweiler, C., Herrmann, F. R., Fantino, B., Brugg, B., & Beauchet, O. (2012) · Cognitive and Behavioral Neurology · doi:10.1097/wnn.0b013e31826df647 · Cited by 104 · see citing works
Cdk5: One of the links between senile plaques and neurofibrillary tangles?
Lee, M.-S., & Tsai, L. (2003) · Journal of Alzheimer s Disease · doi:10.3233/jad-2003-5207 · Cited by 104 · see citing works
A pilot study of the clinical efficacy and safety of memantine for Huntington's disease
Ondo, W. G., Mejia, N. I., & Hunter, C. (2007) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2006.08.005 · Cited by 100 · see citing works
Tau-mediated synaptic damage in Alzheimer’s disease
Jadhav, S., Cubinkova, V., Zimova, I., Brezováková, V., Maďari, A., Cigánková, V., & Žilka, N. (2015) · Translational Neuroscience · doi:10.1515/tnsci-2015-0023 · Cited by 95 · see citing works
Amyloid-β Induces Hepatic Insulin Resistance by Activating JAK2/STAT3/SOCS-1 Signaling Pathway
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Soluble Aβ levels correlate with cognitive deficits in the 12-month-old APPswe/PS1dE9 mouse model of Alzheimer's disease
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In vivo regulation of GSK3 phosphorylation by cholinergic and NMDA receptors
Sarno, P. D., Bijur, G. N., Zmijewska, A. A., Li, X., & Jope, R. S. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.03.003 · Cited by 81 · see citing works
Amyloid-β Induces Hepatic Insulin Resistance In Vivo via JAK2
Zhang, Y., Zhou, B. Z., Deng, B., Zhang, F., Wu, J., Wang, Y., Le, Y., & Zhai, Q. (2012) · Diabetes · doi:10.2337/db12-0670 · Cited by 81 · see citing works
Alzheimer disease‐like clinical phenotype in a family with FTDP‐17 caused by a MAPT R406W mutation
Lindquist, S. G., Holm, I. E., Schwartz, M., Law, I. G., Stokholm, J., Batbayli, M., Waldemar, G., & Nielsen, J. E. (2008) · European Journal of Neurology · doi:10.1111/j.1468-1331.2008.02069.x · Cited by 80 · see citing works
Pharmacological Properties of Glutamatergic Drugs Targeting NMDA Receptors and their Application in Major Depression
Serafini, G., Pompili, M., Innamorati, M., Dwivedi, Y., Brahmachari, G., & Girardi, P. (2013) · Current Pharmaceutical Design · doi:10.2174/13816128113199990293 · Cited by 78 · see citing works
Accuracy of hippocampal network activity is disrupted by neuroinflammation: rescue by memantine
Rosi, S., Ramı́rez-Amaya, V., Vazdarjanova, A. I., Esparza, E. E., Larkin, P. B., Fike, J. R., Wenk, G. L., & Barnes, C. A. (2009) · Brain · doi:10.1093/brain/awp148 · Cited by 76 · see citing works
Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales
Clark, I. A., Atwood, C., Bowen, R. L., Paz-Filho, G., & Vissel, B. (2012) · Pharmacological Reviews · doi:10.1124/pr.112.005850 · Cited by 75 · see citing works
Plasma Aβ42 correlates positively with increased body fat in healthy individuals
Balakrishnan, K., Verdile, G., Mehta, P. D., Beilby, J. P., Nolan, D. A., Galvao, D. A., Newton, R. U., Gandy, S., & Martins, R. N. (2005) · Journal of Alzheimer s Disease · doi:10.3233/jad-2005-8305 · Cited by 74 · see citing works
Memantine upregulates BDNF and prevents dopamine deficits in SIV-infected macaques: a novel pharmacological action of memantine
for the German Competence Network HIV/AIDS, Meisner, F., Scheller, C., Kneitz, S., Sopper, S., Neuen-Jacob, E., Riederer, P., Meulen, V. T., & Koutsilieri, E. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301615 · Cited by 73 · see citing works
Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease
Bordji, K., Becerril-Ortega, J., & Buisson, A. (2011) · Reviews in the Neurosciences · doi:10.1515/rns.2011.029 · Cited by 72 · see citing works
Current Practices in the Treatment of Alzheimer Disease: Where is the Evidence After the Phase III Trials?
Ehret, M. J., & Chamberlin, K. W. (2015) · Clinical Therapeutics · doi:10.1016/j.clinthera.2015.05.510 · Cited by 70 · see citing works
An update on drug treatment options of Alzheimer's disease
Allgaier, M. (2014) · Frontiers in bioscience · doi:10.2741/4285 · Cited by 69 · see citing works
Tolerability and efficacy of memantine add-on therapy to rivastigmine transdermal patches in mild to moderate Alzheimer's disease: a multicenter, randomized, open-label, parallel-group study
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A Tale of the Good and Bad: Remodeling of the Microtubule Network in the Brain by Cdk5
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Potential role of the combination of galantamine and memantine to improve cognition in schizophrenia
Koola, M. M., Buchanan, R. W., Pillai, A., Aitchison, K. J., Weinberger, D. R., Aaronson, S. T., & Dickerson, F. (2014) · Schizophrenia Research · doi:10.1016/j.schres.2014.04.037 · Cited by 62 · see citing works
Memantine for dementia
Areosa, S. A., & Sherriff, F. (2003) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd003154 · Cited by 60 · see citing works
A randomized, double-blind, placebo-controlled trial of memantine in a behaviorally enriched sample of patients with moderate-to-severe Alzheimer's disease
Herrmann, N., Gauthier, S. G., Boneva, N., & Lemming, O. M. (2013) · International Psychogeriatrics · doi:10.1017/s1041610213000239 · Cited by 58 · see citing works
Memantine improves spatial learning and memory impairments by regulating NGF signaling in APP/PS1 transgenic mice
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Involvement of PKA, MAPK/ERK and CaMKII, but not PKC in the acute antidepressant-like effect of memantine in mice
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Reciprocal disruption of neuronal signaling and Aβ production mediated by extrasynaptic NMDA receptors: a downward spiral
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The Role of Insulin Resistance and Glucose Metabolism Dysregulation in the Development of Alzheimer's Disease
Arrieta‐Cruz, I., & Juárez, R. G. (2016) · Revista de investigaci�n Cl�nica · doi:10.1016/s0034-8376(25)00208-6 · Cited by 47 · see citing works
Efficacy and safety profile of memantine in patients with cognitive impairment in multiple sclerosis: A randomized, placebo-controlled study
Peyro‐Saint‐Paul, L., Créveuil, C., Heinzlef, O., Seze, J. D., Vermersch, P., Castelnovo, G., Cabre, P., Debouverie, M., Brochet, B., Dupuy, B., et al. (2016) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2016.02.012 · Cited by 46 · see citing works
Memantine reduces the production of amyloid-β peptides through modulation of amyloid precursor protein trafficking
Ito, K., Tatebe, T., Suzuki, K., Hirayama, T., Hayakawa, M., Kubo, H., Tomita, T., & Makino, M. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.02.001 · Cited by 45 · see citing works
Vitamin D supplements: a novel therapeutic approach for Alzheimer patients
Annweiler, C., Karras, S. Ν., Anagnostis, P. G., & Beauchet, O. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00006 · Cited by 41 · see citing works
Amantadine and memantine induce the expression of the glial cell line-derived neurotrophic factor in C6 glioma cells
Caumont, A., Octave, J., & Hermans, E. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2005.10.027 · Cited by 41 · see citing works
Clinical experience with risperidone and memantine in the treatment of Huntington's disease.
Cankurtaran, E. Ş., Özalp, E., Soygür, H., & Cakir, A. (2006) · PubMed Central · Cited by 41 · see citing works
Effect of memantine combination therapy on symptoms in patients with moderate-to-severe depressive disorder: randomized, double-blind, placebo-controlled study
Amidfar, M., Khiabany, M., Kohi, A., Salardini, E., Arbabi, M., Azizi, M. R., Zarrindast, M., Mohammadinejad, P., Zeinoddini, A., & Akhondzadeh, S. (2016) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/jcpt.12469 · Cited by 40 · see citing works
Alzheimer’s Disease: Genetic Polymorphisms and Rate of Decline
Schmidt, C., Wolff, M., von Ahsen, N., & Zerr, I. (2012) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000336790 · Cited by 38 · see citing works
The Inhibition of Inwardly Rectifying K+Channels by Memantine in Macrophages and Microglial Cells
Tsai, K.-L., Chang, H.-F., & Wu, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350112 · Cited by 37 · see citing works
In vitro galantamine-memantine co-application: Mechanism of beneficial action
Zhao, X., Marszalec, W., Tóth, P. T., Huang, J. C., Yeh, J. Z., & Narahashi, T. (2006) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.08.007 · Cited by 37 · see citing works
Effects of dextromethorphan as add‐on to sitagliptin on blood glucose and serum insulin concentrations in individuals with type 2 diabetes mellitus: a randomized, placebo‐controlled, double‐blinded, multiple crossover, single‐dose clinical trial
Marquard, J., Stirban, A. O., Schliess, F., Sievers, F., Welters, A., Otter, S., Fischer, A., Wnendt, S., Meißner, T., Heise, T., et al. (2015) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12576 · Cited by 36 · see citing works
Repeated co-treatment with fluoxetine and amantadine induces brain-derived neurotrophic factor gene expression in rats.
Rogóż, Z., Skuza, G., & Legutko, B. (2008) · PubMed · Cited by 36 · see citing works
Cognitive benefits of memantine in Alzheimer's 5XFAD model mice decline during advanced disease stages
Devi, L., & Ohno, M. (2016) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2016.03.002 · Cited by 34 · see citing works
Effect of co-administration of memantine and sertraline on the antidepressant-like activity and brain-derived neurotrophic factor (BDNF) levels in the rat brain
Amidfar, M., Réus, G. Z., Quevedo, J., Kim, Y., & Arbabi, M. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.11.003 · Cited by 34 · see citing works
Combined treatment with memantine and galantamine‐CR compared with galantamine‐CR only in antidementia drug naïve patients with mild‐to‐moderate Alzheimer's disease
Peters, O., Fuentes, M., Joachim, L. K., Jessen, F., Luckhaus, C., Kornhuber, J., Pantel, J., Hüll, M., Schmidtke, K., Rüther, E., et al. (2015) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2015.10.001 · Cited by 33 · see citing works
Combined treatment with memantine/es‐citalopram for older depressed patients with cognitive impairment: a pilot study
Pelton, G. H., Harper, O. L., Roose, S. P., Marder, K. S., D’Antonio, K., & Devanand, D. P. (2015) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.4375 · Cited by 32 · see citing works
Alzheimer’s Disease: Lessons Learned from Amyloidocentric Clinical Trials
Soejitno, A., Tjan, A., & Purwata, T. E. (2015) · CNS Drugs · doi:10.1007/s40263-015-0257-8 · Cited by 31 · see citing works
Effects of memantine on mitochondrial function
McAllister, J., Ghosh, S., Berry, D., Park, M., Sadeghi, S., Wang, K. X., Parker, W. D., & Swerdlow, R. H. (2007) · Biochemical Pharmacology · doi:10.1016/j.bcp.2007.10.019 · Cited by 31 · see citing works
Pretreatment with Memantine Prevents Alzheimer-Like Alterations Induced by Intrahippocampal Okadaic Acid Administration in Rats
Zimmer, E. R., Kalinine, E., Haas, C. B., Torrez, V. R., Souza, D. O., Muller, A. P., & Portela, L. V. (2012) · Current Alzheimer Research · doi:10.2174/156720512804142877 · Cited by 29 · see citing works
Alois Alzheimer (1864–1915) and the Alzheimer syndrome
Sharma, V., Sourabh, A., & Harkirat, S. (2011) · Journal of Medical Biography · doi:10.1258/jmb.2010.010037 · Cited by 28 · see citing works
Beta cell glutamate receptor antagonists: novel oral antidiabetic drugs?
Wollheim, C. B., & Maechler, P. (2015) · Nature Medicine · doi:10.1038/nm.3835 · Cited by 28 · see citing works
Effect of Rivastigmine or Memantine Add-on Therapy Is Affected by Butyrylcholinesterase Genotype in Patients with Probable Alzheimer's Disease
Han, H. J., Kwon, J. C., Kim, J. E., Kim, S. G., Park, J., Park, K. W., Park, K., Park, K. H., Moon, S. Y., Seo, S. W., et al. (2014) · European Neurology · doi:10.1159/000366198 · Cited by 23 · see citing works
Response to Rivastigmine Transdermal Patch or Memantine plus Rivastigmine Patch is affected by Apolipoprotein E Genotype in Alzheimer Patients
Han, H. J., Kim, B. C., Lee, J., Ryu, S., Na, H. R., Yoon, S. J., Park, H. Y., Shin, J. H., Cho, S., Yi, H.-A., et al. (2012) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000342927 · Cited by 21 · see citing works
Acetylcholinesterase inhibitors and memantine in bipolar disorder: A systematic review and best evidence synthesis of the efficacy and safety for multiple disease dimensions
Veronese, N., Solmi, M., Luchini, C., Lu, R., Stubbs, B., Zaninotto, L., & Correll, C. U. (2016) · Journal of Affective Disorders · doi:10.1016/j.jad.2016.03.034 · Cited by 20 · see citing works
Cognitive changes under memantine according to vitamin D status in Alzheimer patients: An exposed/unexposed cohort pilot study
Lemire, P., Brangier, A., Beaudenon, M., Duval, G. T., & Annweiler, C. (2016) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2016.12.019 · Cited by 19 · see citing works
Memantine does not show intracellular block of the NMDA receptor channel
Parsons, C. G., Gilling, K. E., & Jatzke, C. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.03.053 · Cited by 18 · see citing works
Cognitive effects of memantine in postmenopausal women at risk of dementia: a pilot study
Wroolie, T., Kenna, H. A., Williams, K. E., Powers, B. N., Holcomb, M. G., Lazzeroni, L. C., & Rasgon, N. (2008) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.2008.01084.x · Cited by 14 · see citing works
Acute Exposure of the Mediobasal Hypothalamus to Amyloid-β 25-35 Perturbs Hepatic Glucose Metabolism
Arrieta‐Cruz, I., Knight, C. M., & Juárez, R. G. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-131865 · Cited by 10 · see citing works
Need for Better Diabetes Treatment: The Therapeutic Potential of NMDA Receptor Antagonists
Welters, A., Lammert, E., Mayatepek, E., & Meißner, T. (2016) · Klinische Pädiatrie · doi:10.1055/s-0042-117831 · Cited by 8 · see citing works
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Han, H. J., Cho, S., Shin, J., Kwon, J. C., Kim, J. E., Kim, S. G., Park, J., Park, K. W., Park, K., Park, K. H., et al. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2014.05.1592 · Cited by 7 · see citing works

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Research works printed but not linked: 7

Areosa SA, 2003, Cochrane Database Syst Rev, 3, CD003154
Llorens-Martìn M, 2014, Front Mol Neurosci, 7, 46
Rogóz Z1, 2008, Pharmacol Rep, 60, 817
Welters A, 2017, Klin Padiatr, 229, 14
Arrieta-Cruz I, 2016, Rev Invest Clin, 68, 53
Lemire P, 2017, J Steroid Biochem Mol Biol
Cankurtaran ES, 2006, J Natl Med Assoc, 98, 1353

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Retracted
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“Memantine showed promising anti-Alzheimer effects in preclinical experimental models, however, in clinical studies, it has not shown clear therapeutic efficacy in AD [33].”
Background
New Insights into Neuroinflammation Involved in Pathogenic Mechanism of Alzheimer’s Disease and Its Potential for Therapeutic Intervention
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Authors: Folch, J., Busquets, O., Ettcheto, M., Sánchez-López, E., Castro-Torres, R. D., Verdaguer, E., Garcia, M. L., Olloquequi, J., Casadesús, G., Beas-Zarate, C., Pelegri, C., Vilaplana, J., Auladell, C., & Camins, A.
Affiliations: Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Unitat de Farmàcia, Tecnologia Farmacèutica i Fisico-química, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Barcelona, Spain
Universidad Autónoma de Chile (CL)
Kent State University (US)
Departamento de Biología Celular y Molecular, Laboratorio de Regeneración y Desarrollo Neural, Instituto de Neurobiología, CUCBA, México
Corresponding author: Camins, Antoni
ORCID: Folch, Jaume
Busquets, Oriol
Ettcheto, Miren
Castro-Torres, Ruben Dario
Verdaguer, Ester
Olloquequi, Jordi
Casadesús, Gemma
Vilaplana, Jordi
Auladell, Carme
Camins, Antoni
Venue: Journal of Alzheimer s Disease
Publisher: SAGE Publications
Published: 2017-12-15
Volume: 62
Issue: 3
Pages: 1223-1240
ISSN: 1387-2877 (ISSN-L)
1875-8908
DOI: 10.3233/jad-170672
PMC: PMC5870028
OpenAlex: W2775709378
Cited by: 245
References: 135
Citations by year: 2026: 23 · 2025: 27 · 2024: 24 · 2023: 31 · 2022: 39 · 2021: 39 · 2020: 36 · 2019: 15 · 2018: 11
FWCI: 2.08
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
creativecommons.org/licenses/by-nc/4.0/ (unspecified)
Locations: Journal of Alzheimer s Disease (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion)
Rovira & Virgili repository (submittedVersion, cc-by)
Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
Funders: Generalitat de Catalunya (2014SGR‐525, 2014SGR-1023, 2014SGR)
Consejo Nacional de Ciencia y Tecnología (298337, 0177594, 000091)
Ministerio de Ciencia e Innovación (MAT 2014-59134R, PI2016/01, 2014-59134-R, CB06/05/0024, 2014SGR-1023)
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (PI2016/01, CB06/05/0024)
National Institute on Aging (R15AG050292)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: memantine, Alzheimer's disease
MeSH terms: Alzheimer Disease, Animals, Humans, Memantine, Neuroprotective Agents

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Memantine for the Treatment of Dementia: A Review on its Current and Future Applications

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