AXS-05: an investigational treatment for Alzheimer’s disease-associated agitation

References

• Cummings J, Mintzer J, Brodaty H, et al. Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. Int Psychogeriatr. 2015;27(1):7–17.
   PubMed Web of Science ®Google Scholar
• Zhao Q-F, Tan L, Wang H-F, et al. The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: systematic review and meta-analysis. J Affect Disord. 2016;190:264–271.
   PubMed Web of Science ®Google Scholar
• Carrarini C, Russo M, Dono F, et al. Agitation and dementia: prevention and treatment strategies in acute and chronic conditions. Front Neurol. 2021;12:644317.
   PubMed Web of Science ®Google Scholar
• Spalletta G, Musicco M, Padovani A, et al. Neuropsychiatric symptoms and syndromes in a large cohort of newly diagnosed, untreated patients with Alzheimer disease. Am J Geriatr Psychiatry. 2010;18(11):1026–1035.
   PubMed Web of Science ®Google Scholar
• Yaffe K, Fox P, Newcomer R, et al. Patient and caregiver characteristics and nursing home placement in patients with dementia. JAMA. 2002;287(16):2090–2097.
   PubMed Web of Science ®Google Scholar
• Wetzels RB, Zuidema SU, Jonghe JFM, et al. Determinants of quality of life in nursing home residents with dementia. Dement Geriatr Cogn Disord. 2010;29(3):189–197.
   PubMed Web of Science ®Google Scholar
• Clyburn LD, Stones MJ, Hadjistavropoulos T, et al. Predicting caregiver burden and depression in Alzheimer’s disease. J Gerontol B Psychol Sci Soc Sci. 2000;55:S2–13.
   PubMed Web of Science ®Google Scholar
• Schumann C, Alexopoulos P, Perneczky R. Determinants of self- and carer-rated quality of life and caregiver burden in Alzheimer disease. Int J Geriatr Psychiatry. 2019;34(10):1378–1385.
   PubMed Web of Science ®Google Scholar
• Alzheimer’s Association. Alzheimer’s disease facts and figures [Internet]. 2022. Available from: https://www.alz.org/media/Documents/alzheimers-facts-and-figures.pdf
   Google Scholar
• Lyketsos CG, Colenda CC, Beck C, et al. Position statement of the American Association for Geriatric psychiatry regarding principles of care for patients with dementia resulting from Alzheimer disease. Am J Geriatr Psychiatry. 2006;14(7):561–572.
   PubMed Web of Science ®Google Scholar
• Davies SJ, Burhan AM, Kim D, et al. Sequential drug treatment algorithm for agitation and aggression in Alzheimer’s and mixed dementia. J Psychopharmacol Oxf Engl. 2018;32(5):509–523.
   PubMed Web of Science ®Google Scholar
• Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry. 2006;14(3):191–210.
   PubMed Web of Science ®Google Scholar
• Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005;294(15):1934–1943.
   PubMed Web of Science ®Google Scholar
• Porsteinsson AP, Drye LT, Pollock BG, et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014;311(7):682–691.
   PubMed Web of Science ®Google Scholar
• Banerjee S, High J, Stirling S, et al. Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial. Lancet Lond Engl. 2021;398(10310):1487–1497.
   PubMed Web of Science ®Google Scholar
• Defrancesco M, Marksteiner J, Fleischhacker WW, et al. Use of benzodiazepines in Alzheimer’s disease: a systematic review of literature. Int J Neuropsychopharmacol. 2015;18(10):yv055.
   Google Scholar
• Liu KY, Borissova A, Mahmood J, et al. Pharmacological treatment trials of agitation in Alzheimer’s disease: a systematic review of ClinicalTrials.gov registered trials. Alzheimers Dement. 2021;7:e12157.
   Google Scholar
• Khoury. Deuterated dextromethorphan/quinidine for agitation in Alzheimer’s disease [Internet]. [cited 2022 Jan 21]. Available from: https://www.nrronline.org/article.asp?=1673-5374;year=2022;volume=17;issue=5;spage=1013;epage=1014;aulast=Khoury.
   Google Scholar
• Avanir Pharmaceuticals, Inc. Reports phase 3 data evaluating investigational AVP-786 for the treatment of moderate-to-severe agitation in patients with Alzheimer’s dementia | Avanir Pharmaceuticals Inc. [Internet]. [cited 2022 Apr 11]. Available from: https://www.avanir.com/press/avanir-pharmaceuticals-inc-reports-phase-3-data-evaluating-investigational-avp-786-treatment.
   Google Scholar
• Cummings JL, Lyketsos CG, Peskind ER, et al. Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia: a randomized clinical trial. JAMA. 2015;314(12):1242–1254.
   PubMed Web of Science ®Google Scholar
• Garay RP, Grossberg GT. AVP-786 for the treatment of agitation in dementia of the Alzheimer’s type. Expert Opin Investig Drugs. 2017;26(1):121–132.
   PubMed Web of Science ®Google Scholar
• Oh S, Agrawal S, Sabir S, et al. Dextromethorphan. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 [cited 2022 Feb 3]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK538216/
   Google Scholar
• Burroughs wellcome to relaunch antidepressant wellbutrin in Mid-July after aborted launch in 1986; FDA-approved labeling includes data on seizure risk. [Internet]. Pink Sheet. 1989 [cited 2022 Mar 31]. Available from: https://pink.pharmaintelligence.informa.com/PS015845/BURROUGHS-WELLCOME-TO-RELAUNCH-ANTIDEPRESSANT-WELLBUTRIN-IN-MIDJULY-AFTER-ABORTED-LAUNCH-IN-1986-FDAAPPROVED-LABELING-INCLUDES-DATA-ON-SEIZURE-RISK
   Google Scholar
• Huecker MR, Smiley A, Saadabadi A. Bupropion. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 [cited 2022 Mar 31]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK470212/
   Google Scholar
• Nguyen L, Thomas KL, Lucke-Wold BP, et al. Dextromethorphan: an update on its utility for neurological and neuropsychiatric disorders. Pharmacol Ther. 2016;159:1–22.
   PubMed Web of Science ®Google Scholar
• Bortolotti F, Bertaso A, Gottardo R, et al. Dextromethorphan/levomethorphan issues in a case of opiate overdose. Drug Test Anal. 2013;5(9–10):781–784.
   PubMed Web of Science ®Google Scholar
• Khan SR, Berendt RT, and Ellison CD, et al. Bupropion hydrochloride. Profiles Drug Subst Excip Relat Methodol. 2016;41:1–30.
   PubMedGoogle Scholar
• Taylor CP, Traynelis SF, and Siffert J, et al. Pharmacology of dextromethorphan: relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacol Ther. 2016;164:170–182.
   PubMed Web of Science ®Google Scholar
• Ferrer-Montiel AV, Merino JM, Planells-Cases R, et al. Structural determinants of the blocker binding site in glutamate and NMDA receptor channels. Neuropharmacology. 1998;37(2):139–147.
   PubMedGoogle Scholar
• Romanelli F, Smith KM. Dextromethorphan abuse: clinical effects and management. J Am Pharm Assoc. 2009;49(2):e20-25; quiz e26–27.
   Google Scholar
• Damaj MI, Flood P, Ho KK, et al. Effect of dextrometorphan and dextrorphan on nicotine and neuronal nicotinic receptors: in vitro and in vivo selectivity. J Pharmacol Exp Ther. 2005;312(2):780–785.
   PubMedGoogle Scholar
• Hernandez SC, Bertolino M, Xiao Y, et al. Dextromethorphan and its metabolite dextrorphan block alpha3beta4 neuronal nicotinic receptors. J Pharmacol Exp Ther. 2000;293(3):962–967.
   PubMed Web of Science ®Google Scholar
• Shin E-J, Nah S-Y, Chae JS, et al. Dextromethorphan attenuates trimethyltin-induced neurotoxicity via σ1 receptor activation in rats. Neurochem Int. 2007;50(6):791–799.
   PubMed Web of Science ®Google Scholar
• Klouz A, Sapena R, Liu J, et al. Evidence for sigma-1-like receptors in isolated rat liver mitochondrial membranes. Br J Pharmacol. 2002;135(7):1607–1615.
   PubMedGoogle Scholar
• Werling LL, Keller A, Frank JG, et al. A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder. Exp Neurol. 2007;207(2):248–257.
   PubMed Web of Science ®Google Scholar
• Pubill D, Gasulla D, Sureda FX, et al. Characterization of [3H]nisoxetine binding in rat vas deferens membranes: modulation by sigma and PCP ligands. Life Sci. 1998;62(8):763–773.
   PubMedGoogle Scholar
• Fryer JD, Lukas RJ. Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine. J Pharmacol Exp Ther. 1999;288(1):88–92.
   PubMed Web of Science ®Google Scholar
• Foley KF, Cozzi NV. Inhibition of transport function and desipramine binding at the human noradrenaline transporter by N-ethylmaleimide and protection by substrate analogs. Naunyn Schmiedebergs Arch Pharmacol. 2002;365(6):457–461.
   PubMedGoogle Scholar
• Mortensen OV, Amara SG. Gain of function mutants reveal sites important for the interaction of the atypical inhibitors benztropine and bupropion with monoamine transporters. J Neurochem. 2006;98(5):1531–1540.
   PubMedGoogle Scholar
• Stathis M, Scheffel U, Lever SZ, et al. Rate of binding of various inhibitors at the dopamine transporter in vivo. Psychopharmacology (Berl). 1995;119(4):376–384.
   PubMedGoogle Scholar
• Arias HR. Is the inhibition of nicotinic acetylcholine receptors by bupropion involved in its clinical actions? Int J Biochem Cell Biol. 2009;41(11):2098–2108.
   PubMed Web of Science ®Google Scholar
• Warner C, Shoaib M. How does bupropion work as a smoking cessation aid? Addict Biol. 2005;10(3):219–231.
   PubMedGoogle Scholar
• Capon DA, Bochner F, Kerry N, et al. The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans. Clin Pharmacol Ther. 1996;60(3):295–307.
   PubMed Web of Science ®Google Scholar
• Kukanich B, Papich MG. Plasma profile and pharmacokinetics of dextromethorphan after intravenous and oral administration in healthy dogs. J Vet Pharmacol Ther. 2004;27(5):337–341.
   PubMedGoogle Scholar
• Pope LE, Khalil MH, Berg JE, et al. Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with quinidine in extensive and poor metabolizers. J Clin Pharmacol. 2004;44(10):1132–1142.
   PubMed Web of Science ®Google Scholar
• O’Gorman C, Jones A, Kennon K, et al. AXS-05 for neuropsychiatric disorders: scientific rationale and clinical development [Internet]. 2018. Available from: https://d3dyybxyjb4kyh.cloudfront.net/pdfs/Axsome_AXS_05_Poster_ASCP_5_2018.pdf.
   Google Scholar
• Johnston AJ, Ascher J, Leadbetter R, et al. Pharmacokinetic optimisation of sustained-release bupropion for smoking cessation. Drugs. 2002;62 Suppl 2(Supplement 2):11–24.
   PubMedGoogle Scholar
• Costa R, Oliveira NG, Dinis-Oliveira RJ. Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects. Drug Metab Rev. 2019;51(3):293–313.
   PubMed Web of Science ®Google Scholar
• Loboz KK, Gross AS, Ray J, et al. HPLC assay for bupropion and its major metabolites in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;823(2):115–121.
   PubMedGoogle Scholar
• Golden RN, De Vane CL, Laizure SC, et al. Bupropion in depression. II. The role of metabolites in clinical outcome. Arch Gen Psychiatry. 1988;45(2):145–149.
   PubMed Web of Science ®Google Scholar
• Xue C, Zhang X, Cai W. Prediction of drug-drug interactions with bupropion and its metabolites as CYP2D6 inhibitors using a physiologically-based pharmacokinetic model. Pharmaceutics. 2017;10(1):1.
   Google Scholar
• Eum S, Sayre F, Lee AM, et al. Association of CYP2B6 genetic polymorphisms with bupropion and hydroxybupropion exposure: a systematic review and meta-analysis. Pharmacotherapy. 2022;42(1):34–44.
   PubMedGoogle Scholar
• Desta Z, El-Boraie A, Gong L, et al. PharmVar GeneFocus: CYP2B6. Clin Pharmacol Ther. 2021;110:82–97.
   PubMed Web of Science ®Google Scholar
• Hayford KE, Patten CA, Rummans TA, et al. Efficacy of bupropion for smoking cessation in smokers with a former history of major depression or alcoholism. Br J Psychiatry J Ment Sci. 1999;174(2):173–178.
   PubMedGoogle Scholar
• Preskorn SH. Antidepressant response and plasma concentrations of bupropion. J Clin Psychiatry. 1983;44(5 Pt 2):137–139.
   PubMed Web of Science ®Google Scholar
• Goodnick PJ. Blood levels and acute response to bupropion. Am J Psychiatry. 1992;149:399–400.
   PubMed Web of Science ®Google Scholar
• DailyMed. BUPROPION HYDROCHLORIDE (SR)- bupropion hydrochloride tablet, film coated, extended release [Internet]. [cited 2022 May 24]. Available from: https://dailymed.awsprod.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1a2a5385-ec04-448f-8bdb-d1cc3eb5f1c0
   Google Scholar
• DailyMed - BUPROPION HYDROCHLORIDE tablet, film coated. [Internet]. [cited 2022 May 24]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c46845ee-ed1c-4788-882c-b9a84ff88bab
   Google Scholar
• O’Gorman C, Iosifescu DV, Jones A, et al. Clinical development of AXS-05 for treatment resistant depression and agitation associated with Alzheimer’s disease [Internet]. Available from: https://d3dyybxyjb4kyh.cloudfront.net/pdfs/Axsome-AXS-05-Poster-APA-2018.pdf
   Google Scholar
• O’Gorman C, Jones A, Cummings JL, et al. Efficacy and safety of AXS-05, a novel oral NMDA receptor antagonist with multimodal activity, in the treatment of Alzheimer’s disease agitation: results of the ADVANCE-1 trial [Internet]. 2020 [cited 2022 Mar 3]. Available from: https://d3dyybxyjb4kyh.cloudfront.net/pdfs/Axsome_AXS-05-Poster-Presentation_CTAD-2020.pdf
   Google Scholar
• Axsome Therapeutics, Inc. A double-blind, placebo-controlled, randomized withdrawal trial to assess the efficacy and safety of AXS-05 for the treatment of agitation in subjects with dementia of the Alzheimer’s type [Internet]. clinicaltrials.gov; Report No.: NCT04797715; 2022 [cited 2022 Apr 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04797715
   Google Scholar
• The ACCORD Study for Alzheimer’s [Internet]. [cited 2022 Apr 5]. Available from: http://accord-study.com/
   Google Scholar
• Axsome Therapeutics, Inc. An open-label study to assess the long-term safety and efficacy of AXS-05 in subjects with Dementia of the Alzheimer’s type [Internet]. clinicaltrials.gov; Report No.: NCT04947553; 2021 [cited 2022 Apr 4]. Available from: https://clinicaltrials.gov/ct2/show/NCT04947553
   Google Scholar
• Yang H, Hong W, Chen L, et al. Analysis of risk factors for depression in Alzheimer’s disease patients. Int J Neurosci. 2020;130(11):1136–1141.
   PubMedGoogle Scholar
• O’Gorman C, Jones A, Iosifescu DV, et al. Rapid effects of AXS-05, an oral NMDA receptor antagonist, in major depressive disorder: results from two randomized, double-blind, controlled trials. Biol Psychiatry. 2021;89(9):S244.
   Google Scholar
• Jones A, O’Gorman C Sustained efficacy with long-term treatment with AXS-05: results from the COMET Phase 3 trial, a long-term, open-label study evaluating the efficacy and safety of AXS-05 for the treatment of MDD [Internet]. Available from: https://d3dyybxyjb4kyh.cloudfront.net/pdfs/ASCP+2021+COMET+overall+poster+FINAL.pdf.
   Google Scholar
• Kammerlind A-SC, Ernsth Bravell M, Fransson EI. Prevalence of and factors related to mild and substantial dizziness in community-dwelling older adults: a cross-sectional study. BMC Geriatr. 2016;16(1):159.
   PubMedGoogle Scholar
• Lindell E, Kollén L, Johansson M, et al. Dizziness and its association with walking speed and falls efficacy among older men and women in an urban population. Aging Clin Exp Res. 2020;32(6):1049–1056.
   PubMed Web of Science ®Google Scholar
• Steinert T, Fröscher W. Epileptic seizures under antidepressive drug treatment: systematic review. Pharmacopsychiatry. 2018;51(4):121–135.
   PubMedGoogle Scholar
• Asadollahi M, Atazadeh M, Noroozian M. Seizure in Alzheimer’s disease: an underestimated phenomenon. Am J Alzheimers Dis Other Demen. 2019;34(2):81–88.
   PubMedGoogle Scholar
• Kumar S, Kodela S, Detweiler JG, et al. Bupropion-induced psychosis: folklore or a fact? A systematic review of the literature. Gen Hosp Psychiatry. 2011;33(6):612–617.
   PubMed Web of Science ®Google Scholar
• Ballard C, Kales HC, Lyketsos C, et al. Psychosis in Alzheimer’s disease. Curr Neurol Neurosci Rep. 2020;20(12):57.
   PubMedGoogle Scholar
• DailyMed - NUEDEXTA- dextromethorphan hydrobromide and quinidine sulfate capsule, gelatin coated [Internet]. [cited 2022 May 24]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=484e0918-3442-49dc-8ccf-177f1f3ee9f3
   Google Scholar
• Volicer L, Citrome L, Volavka J. Measurement of agitation and aggression in adult and aged neuropsychiatric patients: review of definitions and frequently used measurement scales. CNS Spectr. 2017;22(5):407–414.
   PubMedGoogle Scholar