Auvelity as a Potential Treatment for Alzheimer’s Disease
Main Article Content
Abstract
Alzheimer’s disease is the most common form of dementia affecting older adults. Alzheimer’s disease also shares a significant association with Major Depressive Disorder. Glutamatergic excitotoxicity via NMDA receptors is believed to be a key mechanism underlying neurodegeneration in Alzheimer’s Disease. Blockade of NMDA receptors by NMDA antagonists like Memantine appears to inhibit glutamatergic excitotoxicity. Memantine also increases dopaminergic activation through agonism of sigma-1 receptors. The combination of these two mechanisms is believed to underlie Memantine’s improvements in memory, cognition and general functioning in AD patients. Auvelity was recently approved by the FDA for the treatment of Major Depressive Disorder in adults. Auvelity’s relevant mechanism of action is a combination of its blockade of NMDA receptors with consequent antagonism of the glutamatergic neurotransmitter pathway, and its agonism of the sigma-1 receptor. Because Auvelity and AD medications like Memantine employ the same mechanism of action, it is hypothesized that Auvelity might be a potential medical treatment for reducing the symptoms of Alzheimer’s disease.
Keywords:
Auvelity, Alzheimer’s Disease, aging, NMDA antagonist, glutamatergic excitotoxicity
Article Details
How to Cite
LEPKOWSKY, Charles M..
Auvelity as a Potential Treatment for Alzheimer’s Disease.
Medical Research Archives, [S.l.], v. 10, n. 10, oct. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3206>. Date accessed: 26 apr. 2024.
doi: https://doi.org/10.18103/mra.v10i10.3206.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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36. Ryu SH, Jung HY, Lee KJ, Moon SW, Lee DW, Hong N, Kee BS, Kim DH, Han C, Lee CU. Incidence and course of depression in patients with Alzheimer's Disease. Psychiatry Investig. 2017 May;14(3):271-280. doi: 10.4306/pi.2017.14.3.271. Epub 2017 May 16. PMID: 28539945; PMCID: PMC5440429
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39. Strzelecki D, Tabaszewska A, Barszcz Z, Józefowicz O, Kropiwnicki P, Rabe-Jabłońska J. A 10-week memantine treatment in bipolar depression: a case report. Focus on depressive symptomatology, cognitive parameters and quality of life. Psychiatry Investig. 2013 Dec;10(4):421-4. doi: 10.4306/pi.2013.10.4.421. Epub 2013 Dec 16. PMID: 24474993; PMCID: PMC3902162.
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3. Warshaw GA, Bragg EJ. Preparing the health care workforce to care for adults with Alzheimer’s Disease and related dementias. Health Affairs. 2014 Apr;33(4):633-641. doi: https://doi.org/10.1377/hlthaff.2013.1232
4. U.S. Census Bureau. 2014 National Population Projections: Downloadable Files. Available at: https://www.census.gov/data/ datasets/2014/demo/popproj/2014-popproj.html
5. Wragg RE, Jeste DV. Overview of depression and psychosis in Alzheimer's disease. Am J Psychiatry. 1989 May;146(5):577-87. doi: 10.1176/ajp.146.5.577. PMID: 2653053
6. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 2006 May;63(5):530-8. doi: 10.1001/archpsyc.63.5.530. PMID: 16651510; PMCID: PMC3530614
7. Ryu SH, Jung HY, Lee KJ, Moon SW, Lee DW, Hong N, Kee BS, Kim DH, Han C, Lee CU. Incidence and Course of Depression in Patients with Alzheimer's Disease. Psychiatry Investig. 2017 May;14(3):271-280. doi: 10.4306/pi.2017.14.3.271. Epub 2017 May 16. PMID: 28539945; PMCID: PMC5440429
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9. Mathews DC, Henter ID, Zarate CA. Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. Drugs. 2012 Jul 9;72(10):1313-33. doi: 10.2165/11633130-000000000-00000. PMID: 22731961; PMCID: PMC3439647. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439647/
10. Liu J, Chang L, Song Y, Li H, Wu Y. The Role of NMDA Receptors in Alzheimer's Disease. Front Neurosci. 2019 Feb 8;13:43. doi: 10.3389/fnins.2019.00043. PMID: 30800052; PMCID: PMC6375899
11. Zhou Y, Danbolt NC. Glutamate as a neurotransmitter in the healthy brain. J Neural Transm (Vienna). 2014 Aug;121(8):799-817. doi: 10.1007/s00702-014-1180-8. Epub 2014 Mar 1. PMID: 24578174; PMCID: PMC4133642
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13. Johnson JW, Kotermanski SE. Mechanism of action of memantine. Curr Opin Pharmacol. 2006 Feb;6(1):61-7. doi: 10.1016/j.coph.2005.09.007. Epub 2005 Dec 20. PMID: 16368266.
14. Rogawski MA, Wenk GL. The neuropharmacological basis for the use of Memantine in the treatment of Alzheimer's Disease. CNS Drug Reviews. 2003;9(3):275-308. doi: https://doi.org/10.1111/j.1527-3458.2003.tb00254.x
15. Micuda S, Mundlova L, Anzenbacherova E, Anzenbacher P, Chladek J, Fuksa L, Martinkova J. Inhibitory effects of memantine on human cytochrome P450 activities: prediction of in vivo drug interactions. Eur J Clin Pharmacol. 2004 Oct;60(8):583-9. doi: 10.1007/s00228-004-0825-1. Epub 2004 Sep 16. PMID: 15378224.
16. Peeters M, Romieu P, Maurice T, Su TP, Maloteaux JM, Hermans E. Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine. Eur J Neurosci. 2004 Apr;19(8):2212-20. doi: 10.1111/j.0953-816X.2004.03297.x. PMID: 15090047.
17. Wang R, Reddy PH. Role of glutamate and NMDA receptors in Alzheimer's Disease. J Alzheimers Dis. 2017;57(4):1041-1048. doi: 10.3233/JAD-160763. PMID: 27662322; PMCID: PMC5791143. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791143/
18. Haake A, Nguyen K, Friedman L, Chakkamparambil B, Grossberg GT. An update on the utility and safety of cholinesterase inhibitors for the treatment of Alzheimer's disease. Expert Opin Drug Saf. 2020 Feb;19(2):147-157. doi: 10.1080/14740338.2020.1721456. Epub 2020 Jan 28. PMID: 31976781
19. Rosenbaum SB, Gupta V, Palacios JL. Ketamine. [Updated 2022 Jun 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470357/
20. Bortolato M, Godar SC, Melis M, Soggiu A, Roncada P, Casu A, Flore G, Chen K, Frau R, Urbani A, Castelli MP, Devoto P, Shih JC. NMDARs mediate the role of monoamine oxidase A in pathological aggression. J Neurosci. 2012 Jun 20;32(25):8574-82. doi: 10.1523/JNEUROSCI.0225-12.2012. PMID: 22723698; PMCID: PMC3417343. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3417343/
21. Maher P, Davis JB. The role of monoamine metabolism in oxidative glutamate toxicity. J Neurosci. 1996 Oct 15;16(20):6394-6401. doi: https://doi.org/10.1523/JNEUROSCI.16-20-06394.1996
22. Kassubek J, Büttner T, Reichmann H, Riederer P, Schulz JB, Wüllner U, Csoti I. Stellenwert von MAO-B-Inhibitoren und NMDA-Antagonisten in der Therapie des Morbus Parkinson [On the role of MAO B inhibitors and NMDA antagonists in the therapy of Parkinson's disease]. Fortschr Neurol Psychiatr. 2010 Mar;78 Suppl 1:S34-6. German. doi: 10.1055/s-0029-1245166. Epub 2010 Mar 1. PMID: 20195940. https://pubmed.ncbi.nlm.nih.gov/20195940/
23. McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD003154. doi: 10.1002/14651858.CD003154.pub5. Update in: Cochrane Database Syst Rev. 2019 Mar 20;3:CD003154. PMID: 16625572
24. Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov. 2006 Feb;5(2):160-70. doi: 10.1038/nrd1958. PMID: 16424917
25. Ridha BH, Josephs KA, Rossor MN. Delusions and hallucinations in dementia with Lewy bodies: worsening with memantine. Neurology. 2005 Aug 9;65(3):481-2. doi: 10.1212/01.wnl.0000172351.95783.8e. PMID: 16087923
26. Schneider LS, Dagerman KS, Higgins JPT, McShane R. Lack of evidence for the efficacy of Memantine in mild Alzheimer disease. Arch Neurol. 2011;68(8):991–998. doi:10.1001/archneurol.2011.69 https://jamanetwork.com/journals/jamaneurology/fullarticle/1107815
27. Tampi RR, van Dyck CH. Memantine: efficacy and safety in mild-to-severe Alzheimer's disease. Neuropsychiatr Dis Treat. 2007 Apr;3(2):245-58. doi: 10.2147/nedt.2007.3.2.245. PMID: 19300557; PMCID: PMC2654628 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2654628/
28. McShane R, Westby MJ, Roberts E, Minakaran N, Schneider L, Farrimond LE, Maayan N, Ware J, Debarros J. Memantine for dementia. Cochrane Database of Systematic Reviews. 2019;3:CD003154. doi: 10.1002/14651858.CD003154.pub6 https://www.cochrane.org/CD003154/DEMENTIA_memantine-treatment-dementia
29. Ali TB, Schleret TR, Reilly BM, Chen WY, Abagyan R. Adverse effects of cholinesterase inhibitors in dementia, according to the pharmacovigilance databases of the United-States and Canada. PLoS One. 2015 Dec 7;10(12):e0144337. doi: 10.1371/journal.pone.0144337. PMID: 26642212; PMCID: PMC4671709
30. Singh R, Sadiq NM. Cholinesterase Inhibitors. [Updated 2022 Jul 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK544336/
31. AUVELITY [Prescribing Information]. New York, NY: Axsome Therapeutics, Inc. www.axsome.com/auvelity-prescribing-information.pdf
32. Kasper B. Hansen, Feng Yi, Riley E. Perszyk, Hiro Furukawa, Lonnie P. Wollmuth, Alasdair J. Gibb, Stephen F. Traynelis; Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol. 2018 Aug 6;150(8):1081–1105. doi: https://doi.org/10.1085/jgp.201812032
33. Mitani H, Shirayama Y, Yamada T, Maeda K, Ashby CR Jr, Kawahara R. Correlation between plasma levels of glutamate, alanine and serine with severity of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2006 Aug 30;30(6):1155-8. doi: 10.1016/j.pnpbp.2006.03.036. Epub 2006 May 16. PMID: 16707201.
34. Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012 Jan;62(1):63-77. doi: 10.1016/j.neuropharm.2011.07.036. Epub 2011 Aug 3. PMID: 21827775; PMCID: PMC3205453.
35. Peeters M, Romieu P, Maurice T, Su TP, Maloteaux JM, Hermans E. Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine. Eur J Neurosci. 2004 Apr;19(8):2212-20. doi: 10.1111/j.0953-816X.2004.03297.x. PMID: 15090047.
36. Ryu SH, Jung HY, Lee KJ, Moon SW, Lee DW, Hong N, Kee BS, Kim DH, Han C, Lee CU. Incidence and course of depression in patients with Alzheimer's Disease. Psychiatry Investig. 2017 May;14(3):271-280. doi: 10.4306/pi.2017.14.3.271. Epub 2017 May 16. PMID: 28539945; PMCID: PMC5440429
37. Burke AD, Goldfarb D, Bollam P, Khokher S. Diagnosing and treating depression in patients with Alzheimer's Disease. Neurol Ther. 2019 Dec;8(2):325-350. doi: 10.1007/s40120-019-00148-5. Epub 2019 Aug 21. PMID: 31435870; PMCID: PMC6858899
38. Serra G, Demontis F, Serra F, De Chiara L, Spoto A, Girardi P, Vidotto G, Serra G. Memantine: New prospective in bipolar disorder treatment. World J Psychiatry. 2014 Dec 22;4(4):80-90. doi: 10.5498/wjp.v4.i4.80. PMID: 25540723; PMCID: PMC4274590.
39. Strzelecki D, Tabaszewska A, Barszcz Z, Józefowicz O, Kropiwnicki P, Rabe-Jabłońska J. A 10-week memantine treatment in bipolar depression: a case report. Focus on depressive symptomatology, cognitive parameters and quality of life. Psychiatry Investig. 2013 Dec;10(4):421-4. doi: 10.4306/pi.2013.10.4.421. Epub 2013 Dec 16. PMID: 24474993; PMCID: PMC3902162.
40. Lee, SY., Wang, TY., Chen, SL. et al. Combination of dextromethorphan and memantine in treating bipolar spectrum disorder: a 12-week double-blind randomized clinical trial. Int J Bipolar Disord. 2020;8(11). doi: https://doi.org/10.1186/s40345-019-0174-8