pharmaceutical agents for treatment of Alzheimer's disease (Alzheimer's agent)

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Adverse effects

* relative to donepezil

Management

no agent shown to improve clinically relevant outcomes[19]

associated behavioral syndromes

sleep disturbance

others (from 2001 recommendations of the American Academy of Neurology, see early intervention for Alzheimer's disease)

estrogen NOT useful, may be risk

statins may diminish rate of deterioration[14]

centrally-acting ACE inhibitors may diminish rate of deterioration[15][26]

idalopirdine, a 5HT6 receptor antagonist, failed to slow cognitive decline in patients with Alzheimer's disease[39]

cholinesterase inhibitors, memantine, & statins inappropriate in patients with advanced dementia[32]

* FDA proposes approval of new drugs for treatment of preclinical Alzheimer's disease based on changes in biomarkers without demonstration of actual clinical benefit[6]

* NICE (UK) recommends cholinesterase inhibitors & memantine no longer be used for treating Alzheimer's disease. These drugs do NOT delay institutionalization & are NOT cost-effective[8]

* NICE (UK) recommends cholinesterase inhibitor as an option for moderately severe AD (MMSE 10-20)[8]

* NICE does NOT recommend memantine except for clinical trials, OK to continue if currently prescribed medication[8]

* benefits of cholinesterase inhibitors in Alzheimer disease patients are relatively small & likely extend to only a subset of AD patients that can't be identified in advance[11]

* treatment of dementia with cholinesterase inhibitors & memantine can result in statistically significant but clinically marginal improvement in measures of cognition & global assessment of dementia[15]

* neither donepezil nor memantine significantly affects outcomes important to caregivers[22]

* continuing donepezil in patients with moderate-severe AD

* evidence is insufficient to compare the effectiveness of different pharmaceutical agents to treat dementia[15]

Also see cholinesterase inhibitor clinical trials

More general terms

More specific terms

Additional terms

References

  1. ↑ Prescriber's Letter 8(7):40 2001
  2. ↑ 2.0 2.1 www.alz.org
  3. ↑ 3.0 3.1 UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
  4. ↑ Journal Watch 23(4):36, 2003 Trinh N-H et al, JAMA 289:210, 2003
  5. ↑ 5.0 5.1 Tariot PN JAMA 291:317, 2003 http://jama.ama-assn.org/cgi/content/abstract/291/3/317
  6. ↑ 6.0 6.1 MedPage Today Staff. February 15, 2018 Sea Change for Alzheimer's Drug Development (FDA) Agency may approve drugs for 'preclinical' disease solely on biomarker effects. https://www.medpagetoday.com/neurology/alzheimersdisease/71185
    U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Early Alzheimer's Disease: Developing Drugs for Treatment Guidance for Industry. Draft Guidance. February 2018 https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM596728.pdf
  7. ↑ Espinosa R. In: Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 29-Oct 2, 2004
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Internal Medicine News, April 15, 2005, pg 12
  9. ↑ 9.0 9.1 Journal Watch 24(17):133, 2004 Lee PE, Gill SS, Freedman M, Bronskill SE, Hillmer MP, Rochon PA. Atypical antipsychotic drugs in the treatment of behavioural and psychological symptoms of dementia: systematic review. BMJ. 2004 Jul 10;329(7457):75. Epub 2004 Jun 11. Review. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/15194601 <Internet> http://bmj.bmjjournals.com/cgi/content/full/329/7457/75
  10. ↑ 10.0 10.1 FDA Public Health Advisory Deaths with Antipsychotics in Elderly Patients with Behavioral Disturbances http://www.fda.gov/cder/drug/advisory/antipsychotics.htm http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#atypical
  11. ↑ 11.0 11.1 Kaduszkiewicz H et al Cholinesterase inhibitors for patients with Alzheimer's disease: Systematic review of randomised clinical trials. BMJ 2005 Aug 6; 331:321-7. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/16081444 <Internet> http://bmj.bmjjournals.com/cgi/content/full/331/7512/321
  12. ↑ Prescriber's Letter 13(10): 2006 Drug Treatment of Dementia Due to Alzheimer's Disease Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=221005&pb=PRL (subscription needed) http://www.prescribersletter.com
  13. ↑ Schneider LS Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease N Engl J Med 2006, 355:1525 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17035647
    Karlawish J Alzheimer's disease - Clinical trials and the logic of clinical purpose. N Engl J Med 2006, 355:1604 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17035654
  14. ↑ 14.0 14.1 14.2 Ellul J, Archer N, Foy CM, Poppe M, Boothby H, Nicholas H, Brown RG, Lovestone S. The effects of commonly prescribed drugs in patients with Alzheimer's disease on the rate of deterioration. J Neurol Neurosurg Psychiatry. 2007 Mar;78(3):233-9. PMID: https://www.ncbi.nlm.nih.gov/pubmed/17012333
  15. ↑ 15.0 15.1 15.2 15.3 15.4 Qaseem A et al, Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Annals of Internal Medicine 2008, 148:370 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/18316755 <Internet> http://www.annals.org/cgi/content/full/148/5/370 (corresponding NGC guideline withdrawn Jan 2014)
    Raina P et al, Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Annals of Internal Medicine 2008, 148:379 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/18316756 <Internet> http://www.annals.org/cgi/content/full/148/5/379
  16. ↑ Prescriber's Letter 15(5): 2008 Pharmacotherapy Choices for Patients with Dementia CHART: Drugs to Avoid in Patients with Dementia COMMENTARY: Efficacy of Dementia Drugs and Guidelines for Use GUIDELINES: American College of Physicians and the American Academy of Family Physicians Clinical Practice Guideline on Current Pharmacologic Treatment of Dementia Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=240510&pb=PRL (subscription needed) http://www.prescribersletter.com
  17. ↑ 17.0 17.1 17.2 Atri A et al, Long-term course and effectiveness of combination therapy in Alzheimer's disease. Alzheimer Dis Assoc Disord. 2008 Jul-Sep;22(3):209-21. PMID: https://www.ncbi.nlm.nih.gov/pubmed/18580597
  18. ↑ 18.0 18.1 Prescriber's Letter 16(7): 2009 PATIENT HANDOUT: Cholinesterase Inhibitors for Dementia COMMENTARY: Cardiac Effects of Cholinesterase Inhibitors Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=250126&pb=PRL (subscription needed) http://www.prescribersletter.com
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 19.6 19.7 Medical Knowledge Self Assessment Program (MKSAP) 15, 16, 17, 19. American College of Physicians, Philadelphia 2009, 2012, 2015, 2021
  20. ↑ 20.0 20.1 20.2 Schneider LS et al. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol 2011 Apr 11; <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/21482915 <Internet> http://archneur.ama-assn.org/cgi/content/abstract/archneurol.2011.69v1
  21. ↑ 21.0 21.1 Banerjee S et al Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo- controlled trial The Lancet, Early Online Publication, 18 July 2011 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/21764118 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60830-1/abstract
  22. ↑ 22.0 22.1 22.2 22.3 22.4 Howard R et al Donepezil and Memantine for Moderate-to-Severe Alzheimer's Disease. N Engl J Med 2012; 366:893-903March 8, 2012 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22397651 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1106668
    Schneider LS. Discontinuing donepezil or starting memantine for Alzheimer's disease. N Engl J Med. 2012 Mar 8;366(10):957-9 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22397659
    Burke D. ACP Journal Club. Donepezil or memantine improved cognitive functioning in moderate-to-severe Alzheimer disease (EDJ). Ann Intern Med. 19 June 2012; 156(12):JC6-JC10 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22711111
  23. ↑ Prescriber's Letter 19(5): 2012 COMMENTARY: Pharmacotherapy and Advancing Alzheimer's Disease Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=280527&pb=PRL (subscription needed) http://www.prescribersletter.com
  24. ↑ Schneider LS. EDITORIAL. Discontinuing donepezil or starting memantine for Alzheimer's disease. N Engl J Med 2012; 366:957-959 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22397659
  25. ↑ Burke D. ACP Journal Club. Donepezil or memantine improved cognitive functioning in moderate-to-severe Alzheimer disease (EDJ). Ann Intern Med 19 June 2012; 156(12):JC6-JC10 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22711111
  26. ↑ 26.0 26.1 Gao Y, O'Caoimh R, Healy L et al Effects of centrally acting ACE inhibitors on the rate of cognitive decline in dementia. BMJ Open 2013;3:e002881 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23887090 <Internet> http://bmjopen.bmj.com/content/3/7/e002881
  27. ↑ Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alzheimer's disease: clinical trials and drug development. Lancet Neurol. 2010 Jul;9(7):702-16 PMID: https://www.ncbi.nlm.nih.gov/pubmed/20610346
  28. ↑ 28.0 28.1 28.2 Dysken MW et al Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease. The TEAM-AD VA Cooperative Randomized Trial. JAMA. 2014;311(1):33-4 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24381967 <Internet> http://jama.jamanetwork.com/article.aspx?articleid=1810379
    Evans DA et al Vitamin E, Memantine, and Alzheimer Disease. JAMA. 2014;311(1):29-30 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24381966 <Internet> http://jama.jamanetwork.com/article.aspx?articleid=1810360
  29. ↑ O'Brien JT, Burns A; BAP Dementia Consensus Group. Clinical practice with anti-dementia drugs: a revised (second) consensus statement from the British Association for Psychopharmacology. J Psychopharmacol. 2011 Aug;25(8):997-1019. PMID: https://www.ncbi.nlm.nih.gov/pubmed/21088041
  30. ↑ Lopez OL, Becker JT, Wahed AS Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009 Jun;80(6):600-7. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19204022
  31. ↑ 31.0 31.1 Farina N, Isaac MG, Clark AR, et al. Vitamin E for Alzheimer's dementia and mild cognitive impairment. Cochrane Database Syst Rev. 2012; 11:CD002854. PMID: https://www.ncbi.nlm.nih.gov/pubmed/23152215
  32. ↑ 32.0 32.1 Tjia J et al Use of Medications of Questionable Benefit in Advanced Dementia. JAMA Intern Med. Published online September 08, 2014 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25201279 <Internet> http://archinte.jamanetwork.com/article.aspx?articleid=1901117
    Sachs GA Improving Prescribing Practices Late in Life. A Task for all Clinicians, Not Just Nursing Home Physicians. JAMA Intern Med. Published online September 08, 2014. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25200598 <Internet> http://archinte.jamanetwork.com/article.aspx?articleid=1901111
  33. ↑ 33.0 33.1 AGS Choosing Wisely Workgroup. American Geriatrics Society identifies another five things that healthcare providers and patients should question. J Am Geriatr Soc. 2014;62:950-960. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24575770
  34. ↑ Delrieu J, Piau A, Caillaud C, Voisin T, Vellas B. Managing cognitive dysfunction through the continuum of Alzheimer's disease: role of pharmacotherapy. CNS Drugs. 2011 Mar;25(3):213-26 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21323393
  35. ↑ 35.0 35.1 Howard R et al. Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial: Secondary and post-hoc analyses. Lancet Neurol 2015 Oct 26 PMID: https://www.ncbi.nlm.nih.gov/pubmed/26515660
  36. ↑ 36.0 36.1 Vellas B, Coley N, Ousset PJ et al Long-term use of standardised ginkgo biloba extract for the prevention of Alzheimer's disease (GuidAge): a randomised placebo-controlled trial Lancet Neurol. 2012 Oct;11(10):851-9. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/22959217 <Internet> http://www.thelancet.com/journals/laneur/article/PIIS1474-4422%2812%2970206-5/abstract
  37. ↑ 37.0 37.1 Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016
  38. ↑ 38.0 38.1 38.2 38.3 McCleery J, Cohen DA, Sharpley AL. Pharmacotherapies for sleep disturbances in Alzheimer's disease. Cochrane Database Syst Rev. 2014 Mar 21;(3):CD009178. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24659320
  39. ↑ 39.0 39.1 39.2 Fiore K NeuroBreak: Alzheimer's Drug Bombs; Elephant Tranquilizer ODs. MEDPAGE TODAY. Sept 27, 2016 http://www.medpagetoday.com/Neurology/GeneralNeurology/60482
    Fiore K AAIC 2017 Meeting Coverage. 5HT6 Blocker a Dud in Alzheimer Trials - May shake confidence in similar drugs being developed. https://www.medpagetoday.com/MeetingCoverage/AAIC/66784
    Atri A, Frolich L, Ballard C et al Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease. Three Randomized Clinical Trials. JAMA. 2018;319(2):130-142 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29318278 https://jamanetwork.com/journals/jama/article-abstract/2668349
    Bennett DA Lack of Benefit With Idalopirdine for Alzheimer Disease. Another Therapeutic Failure in a Complex Disease Process. JAMA. 2018;319(2):123-125. Jan 9. PMID: https://www.ncbi.nlm.nih.gov/pubmed/29318261 https://jamanetwork.com/journals/jama/article-abstract/2668332
  40. ↑ 40.0 40.1 Lampela P, Tolppanen AM, Tanskanen A et al Use of antidementia drugs and risk of pneumonia in older persons with Alzheimer's disease. Ann Med. 2016 Oct 27:1-25. [Epub ahead of print] PMID: https://www.ncbi.nlm.nih.gov/pubmed/27786552
  41. ↑ 41.0 41.1 Padala PR, Padala KP, Lensing SY et al. Methylphenidate for apathy in community-dwelling older veterans with mild Alzheimer's disease: A double-blind, randomized, placebo-controlled trial. Am J Psychiatry 2017 Sep 15 PMID: https://www.ncbi.nlm.nih.gov/pubmed/28945120
  42. ↑ 42.0 42.1 42.2 Chen R, Chan PT, Chu H et al. Treatment effects between monotherapy of donepezil versus combination with memantine for Alzheimer disease: A meta- analysis. PLoS One 2017 Aug 21; 12:e0183586. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28827830 Free PMC Article <Internet> http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183586
  43. ↑ 43.0 43.1 43.2 Therapeutics Letter #108. Therapeutics Initiative Drugs to Avoid. http://www.ti.ubc.ca/2018/01/04/108-drugs-avoid/
  44. ↑ 44.0 44.1 44.2 Koch G et al Effect of Rotigotine vs Placebo on Cognitive Functions Among Patients With Mild to Moderate Alzheimer Disease. A Randomized Clinical Trial. JAMA Netw Open. 2020;3(7):e2010372 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32667654 Free article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2768248
  45. ↑ 45.0 45.1 45.2 45.3 Oh ES, Rosenberg PB, Rattinger GB et al Psychotropic Medication and Cognitive, Functional, and Neuropsychiatric Outcomes in Alzheimer's Disease (AD) J Am Geriatr Soc. 2021 Apr;69(4):955-963 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33382921
  46. ↑ 46.0 46.1 Borda MG, Jaramillo-Jimenez A, Oesterhus R et al Benzodiazepines and antidepressants: effects on cognitive and functional decline in Alzheimer's disease and Lewy body dementia. Int J Geriatr Psychiatry. 2020 Dec 31. PMID: https://www.ncbi.nlm.nih.gov/pubmed/33382911
  47. ↑ 47.0 47.1 Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005 Jan 4;142(1):37-46. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15537682 Free article
  48. ↑ 48.0 48.1 48.2 Mintzer J,Lanctot KL, Scherer RW et al Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease. The ADMET 2 Randomized Clinical Trial. JAMA Neurol. 2021;78(11):1324-1332. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34570180 PMCID: PMC8477302 (available on 2022-09-27) https://jamanetwork.com/journals/jamaneurology/fullarticle/2784538
    Fredericks C Methylphenidate for Apathy in Alzheimer Disease - Why Should We Care? JAMA Neurol. 2021;78(11):1311-1313. PMID: https://www.ncbi.nlm.nih.gov/pubmed/34570178 https://jamanetwork.com/journals/jamaneurology/fullarticle/2784541
  49. ↑ 49.0 49.1 Zheng X et al Effectiveness and safety of anti-tau drugs for Alzheimer's disease: Systematic review and meta-analysis. J Am Geriatr Soc. 2022 Nov;70(11):3281-3292. ePub 2022 Oct 22 PMID: https://www.ncbi.nlm.nih.gov/pubmed/36208415 Review. https://agsjournals.onlinelibrary.wiley.com/doi/full/10.1111/jgs.18025
  50. ↑ 50.0 50.1 Arvanitakis Z, Shah RC, Bennett DA. Diagnosis and Management of Dementia: Review JAMA. 2019 Oct 22;322(16):1589-1599 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31638686 PMCID: PMC7462122 Free PMC article https://jamanetwork.com/journals/jama/fullarticle/2753376
  51. ↑ 51.0 51.1 NEJM Knowledge+ Psychiatry
  52. ↑ Sims JR, Zimmer JA, Evans CD et al Donanemab in Early Symptomatic Alzheimer Disease. The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. Published online July 17, 2023 PMID: https://www.ncbi.nlm.nih.gov/pubmed/37459141 PMCID: PMC10352931 Free PMC article https://jamanetwork.com/journals/jama/fullarticle/2807533
  53. ↑ 53.0 53.1 53.2 Honig LS, Vellas B, Woodward M et al Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease. N Engl J Med 2018; 378:321-330. Jan 25, 2018 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/29365294 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1705971
  54. ↑ 54.0 54.1 Sperling RA et al. Trial of solanezumab in preclinical Alzheimer's disease. N Engl J Med 2023 Jul 17; PMID: https://www.ncbi.nlm.nih.gov/pubmed/37458272 https://www.nejm.org/doi/10.1056/NEJMoa2305032
  55. ↑ Molchan S, Fugh-Berman A. Are New Alzheimer Drugs Better Than Older Drugs? JAMA Intern Med. 2023;183(9):902-903. July 31 PMID: https://www.ncbi.nlm.nih.gov/pubmed/37523164 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2807943

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