Galantamine-memantine combination superior to donepezil-memantine combination in Alzheimer’s disease: critical dissection with an emphasis on kynurenic acid and mismatch negativity

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Abstract

Background:

The donepezil-memantine combination is a US Food and Drug Administration (FDA)–approved medication to treat Alzheimer’s disease (AD). Galantamine is superior to donepezil because it is a positive allosteric modulator of the alpha-7 nicotinic acetylcholine receptor (α7nAChR). Although galantamine and memantine are both FDA approved for the treatment of AD, the combination is still underutilized in clinical practice.

Aim:

The objective of this review was to critically examine the mechanisms by which the galantamine-memantine combination may be superior to the donepezil-memantine combination in AD by targeting the cholinergic-nicotinic and glutamatergic systems concurrently.

Method:

PubMed and Google Scholar were searched using the keywords Alzheimer’s disease, cholinergic, glutamatergic, α7nAChR, N-methyl-D-aspartate (NMDA) receptors, donepezil, galantamine, memantine, clinical trials, and biomarkers.

Results:

AD is associated with several biomarkers such as kynurenine pathway (KP) metabolites, mismatch negativity (MMN), brain-derived neurotrophic factor (BDNF), and oxidative stress. In several preclinical studies, cognitive impairments significantly improved with the galantamine-memantine combination compared to either medication alone. Synergistic benefits were also seen with the combination. In a randomized controlled trial (RCT) in prodrome AD, cognition significantly improved with the galantamine-memantine combination compared to galantamine alone; cognition declined after galantamine was discontinued. However, in an RCT in AD, cognition did not significantly improve with the galantamine-memantine combination compared to galantamine alone. In a retrospective study in AD, the galantamine-memantine combination significantly improved cognition compared to the donepezil-memantine combination. Galantamine and memantine via the α7nACh and NMDA receptors can counteract the effects of kynurenic acid and enhance MMN and BDNF.

Conclusion:

Future studies with the galantamine-memantine combination with KP metabolites, MMN, and BDNF as biomarkers are warranted. Positive RCTs in AD may lead to FDA approval of the combination, resulting in greater utilization in clinical practice. In the meantime, clinicians may continue to use the galantamine-memantine combination to treat patients with AD.

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Most cited references 92

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Cholinesterase inhibitors for Alzheimer's disease.

Jacqueline S Birks (2016)

Since the introduction of the first cholinesterase inhibitor (ChEI) in 1997, most clinicians and probably most patients would consider the cholinergic drugs, donepezil, galantamine and rivastigmine, to be the first line pharmacotherapy for mild to moderate Alzheimer's disease.The drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase. The most that these drugs could achieve is to modify the manifestations of Alzheimer's disease. Cochrane reviews of each ChEI for Alzheimer's disease have been completed (Birks 2005, Birks 2005b and Loy 2005). Despite the evidence from the clinical studies and the intervening clinical experience the debate on whether ChEIs are effective continues. To assess the effects of donepezil, galantamine and rivastigmine in people with mild, moderate or severe dementia due to Alzheimer's disease. The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' , 'Aricept' , galanthamin* galantamin* reminyl, rivastigmine, exelon, "ENA 713" and ENA-713 on 12 June 2005. This Register contains up-to-date records of all major health care databases and many ongoing trial databases. All unconfounded, blinded, randomized trials in which treatment with a ChEI was compared with placebo or another ChEI for patients with mild, moderate or severe dementia due to Alzheimer's disease. Data were extracted by one reviewer (JSB), pooled where appropriate and possible, and the pooled treatment effects, or the risks and benefits of treatment estimated. The results of 13 randomized, double blind, placebo controlled trials demonstrate that treatment for periods of 6 months and one year, with donepezil, galantamine or rivastigmine at the recommended dose for people with mild, moderate or severe dementia due to Alzheimer's disease produced improvements in cognitive function, on average -2.7 points (95%CI -3.0 to -2.3), in the midrange of the 70 point ADAS-Cog Scale. Study clinicians blind to other measures rated global clinical state more positively in treated patients. Benefits of treatment were also seen on measures of activities of daily living and behaviour. None of these treatment effects are large. There is nothing to suggest the effects are less for patients with severe dementia or mild dementia, although there is very little evidence for other than mild to moderate dementia.More patients leave ChEI treatment groups, approximately 29 %, on account of adverse events than leave the placebo groups (18%). There is evidence of more adverse events in total in the patients treated with a ChEI than with placebo. Although many types of adverse event were reported, nausea, vomiting, diarrhoea, were significantly more frequent in the ChEI groups than in placebo. There are four studies, all supported by one of the pharmaceutical companies, in which two ChEIs were compared, two studies of donepezil compared with galantamine, and two of donepezil compared with rivastigmine. In three studies the patients were not blinded to treatment, only the fourth, DON vs RIV/Bullock is double blind. Two of the studies provide little evidence, they are of 12 weeks duration, which is barely long enough to complete the drug titration. There is no evidence from DON vs GAL/Wilcock of a treatment difference between donepezil and galantamine at 52 weeks for cognition, activities of daily living, the numbers who leave the trial before the end of treatment, the number who suffer any adverse event, or any specific adverse event. There is no evidence from DON vs RIV/Bullock of a difference between donepezil and rivastigmine for cognitive function, activities of daily living and behavioural disturbance at two years. Fewer patients suffer adverse events on donepezil than rivastigmine. The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer's disease. It is not possible to identify those who will respond to treatment prior to treatment. There is no evidence that treatment with a ChEI is not cost effective. Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy. There appears to be less adverse effects associated with donepezil compared with rivastigmine. It may be that galantamine and rivastigmine match donepezil in tolerability if a careful and gradual titration routine over more than three months is used. Titration with donepezil is more straightforward and the lower dose may be worth consideration.

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Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease.

Matthew Hynd, Heather Scott, Peter R Dodd (2004)

Alzheimer's disease (AD) is the most common form of dementia, accounting for 60-70% of cases in subjects over 65 years of age. Several postulates have been put forward that relate AD neuropathology to intellectual and functional impairment. These range from free-radical-induced damage, through cholinergic dysfunction, to beta-amyloid-induced toxicity. However, therapeutic strategies aimed at improving the cognitive symptoms of patients via choline supplementation, cholinergic stimulation or beta-amyloid vaccination, have largely failed. A growing body of evidence suggests that perturbations in systems using the excitatory amino acid L-glutamate (L-Glu) may underlie the pathogenic mechanisms of (e.g.) hypoxia-ischemia, epilepsy, and chronic neurodegenerative disorders such as Huntington's disease and AD. Almost all neurons in the CNS carry the N-methyl-D-aspartate (NMDA) subtype of ionotropic L-glutamate receptors, which can mediate post-synaptic Ca2+ influx. Excitotoxicity resulting from excessive activation of NMDA receptors may enhance the localized vulnerability of neurons in a manner consistent with AD neuropathology, as a consequence of an altered regional distribution of NMDA receptor subtypes. This review discusses mechanisms for the involvement of the NMDA receptor complex and its interaction with polyamines in the pathogenesis of AD. NMDA receptor antagonists have potential for the therapeutic amelioration of AD.

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Kynurenines in the CNS: recent advances and new questions.

László Vécsei, Levente Szalárdy, Ferenc Fülöp … (2013)

Various pathologies of the central nervous system (CNS) are accompanied by alterations in tryptophan metabolism. The main metabolic route of tryptophan degradation is the kynurenine pathway; its metabolites are responsible for a broad spectrum of effects, including the endogenous regulation of neuronal excitability and the initiation of immune tolerance. This Review highlights the involvement of the kynurenine system in the pathology of neurodegenerative disorders, pain syndromes and autoimmune diseases through a detailed discussion of its potential implications in Huntington's disease, migraine and multiple sclerosis. The most effective preclinical drug candidates are discussed and attention is paid to currently under-investigated roles of the kynurenine pathway in the CNS, where modulation of kynurenine metabolism might be of therapeutic value.

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Author and article information

Contributors

Maju Mathew Koola

Agnieszka Nikiforuk

Anilkumar Pillai

Ajay K. Parsaik

Journal

Journal ID (nlm-journal-id): 101736616

Journal ID (pubmed-jr-id): 48108

Journal ID (nlm-ta): J Geriatr Care Res

Journal ID (iso-abbrev): J Geriatr Care Res

Title: Journal of geriatric care and research

ISSN (Electronic): 2397-5628

Publication date Nihms-submitted: 2 November 2018

Publication date (Print): 2018

Publication date PMC-release: 10 April 2019

Volume: 5

Issue: 2

Pages: 57-67

Affiliations

Department of Psychiatry and Behavioral Sciences, George Washington University School of Medicine and Health Sciences, Washington, DC, USA, mkoola@ 123456gwu.edu

Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland, nikifor@ 123456if-pan.krakow.pl

Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta University, Augusta, GA, USA, apillai@ 123456augusta.edu

Department of Psychiatry and Behavioral Health, Marshfield Clinic Health System, Marshfield, WI, USA, drajayparsaik@ 123456gmail.com

Author notes

Correspondence: Maju Mathew Koola, MD, Department of Psychiatry and Behavioral Sciences, George Washington University School of Medicine and Health Sciences, 2300 I St NW, Washington, DC, USA 20037, mkoola@ 123456gwu.edu ; majumkoola@ 123456gmail.com

Article

Manuscript ID: NIHMS992938

PMC ID: 6457262

PubMed ID: 30984874

SO-VID: 7b502ee4-838f-4f02-a0be-0cf20c0ee11e

License:

This is an open-access article distributed under the terms [CC BY-NC] which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Galantamine-memantine combination superior to donepezil-memantine combination in Alzheimer’s disease: critical dissection with an emphasis on kynurenic acid and mismatch negativity

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Abstract

Background:

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Most cited references 92

Cholinesterase inhibitors for Alzheimer's disease.

Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease.

Kynurenines in the CNS: recent advances and new questions.

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