Journal List > J Korean Med Assoc > v.61(12) > 1109395

Youn and Jeong: Pharmacotherapy for dementia

Abstract

Dementia is a clinical syndrome characterized by a cluster of symptoms and signs that manifest as difficulties in cognitive functions such as memory, psychological and psychiatric changes, and impairments in activities of daily living. As a result of worldwide trends of population aging, dementia has had a huge impact on public health in almost all countries. Disease modification therapies for dementia have not yet been developed. However, pharmacotherapy is essential in patients with dementia to combat delays in their cognitive and functional decline. In this article, we review the current pharmacotherapy for dementia. Three acetylcholinesterase inhibitors—donepezil, rivastigmine, galantamine—and memantine are the only medications that have been approved for the treatment of dementia. We present the indications, dose recommendations, side effects, and criteria for National Health Insurance coverage in Korea of these medications for dementia treatment. Although the Ministry of Food and Drug Safety in Korea has not approved any medications for managing the behavioral and psychological symptoms of dementia, some antipsychotics and antidepressants have been studied and used clinically for those purposes. Clinicians may consider vitamin E, Ginkgo biloba extract, choline alfoscerate, or omega-3 fatty acids as additional treatment options. Non-steroid anti-inflammatory drugs, estrogen hormone therapy, and statins are not generally recommended for dementia treatment. We believe that our findings will aid clinicians in the treatment of patients with cognitive decline.

REFERENCES

1. Jeong HG, Han C. Diagnosis and treatment of dementia in primary care. J Korean Med Assoc. 2013; 56:1104–1112.
crossref
2. Xu J, Qiu C. Worldwide economic costs and societal burden of dementia. Perneczky R, editor. editor.Biomarkers for preclinical Alzheimerʼs disease. New York: Springer;2018. p. 3–13.
crossref
3. Ministry of Health and Welfare. Korean dementia observatory 2017. Sejong: Ministry of Health and Welfare;2017.
4. Hahn SJ, Paik NJ. Pharmacological treatment of dementia. Brain Neurorehabil. 2015; 8:19–23.
crossref
5. Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimerʼs disease: a review of progress. J Neurol Neurosurg Psychiatry. 1999; 66:137–147.
crossref
6. Birks J. Cholinesterase inhibitors for Alzheimerʼs disease. Cochrane Database Syst Rev. 2006; 1:CD005593.
crossref
7. Hansen RA, Gartlehner G, Webb AP, Morgan LC, Moore CG, Jonas DE. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimerʼs disease: a systematic review and metaanalysis. Clin Interv Aging. 2008; 3:211–225.
8. Zhu CW, Livote EE, Scarmeas N, Albert M, Brandt J, Blacker D, Sano M, Stern Y. Longterm associations between cholinesterase inhibitors and memantine use and health outcomes among patients with Alzheimerʼs disease. Alzheimers Dement. 2013; 9:733–740.
crossref
9. Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, Edwards S, Hardyman W, Raftery J, Crome P, Lendon C, Shaw H, Bentham P. AD2000 Collaborative Group. Longterm donepezil treatment in 565 patients with Alzheimerʼs disease (AD2000): randomised double-blind trial. Lancet. 2004; 363:2105–2115.
10. Korean Association for Geriatric Psychiatry. Geriatric psychiatry. 2nd ed.Seoul: ML Communication;2015.
11. Mendez MF, Cummings JL. Dementia: a clinical approach. Philadelphia: Butterworth-Heinemann;2003.
12. Ministry of Food and Drug Safety. Online library of medicine [Internet]. Cheongju: Ministry of Food and Drug Safety;2018. [cited 2018 Nov 1]. Available from:. http://drug.mfds.go.kr/html/index.jsp#n.
13. Farlow MR, Salloway S, Tariot PN, Yardley J, Moline ML, Wang Q, Brand-Schieber E, Zou H, Hsu T, Satlin A. Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimerʼs disease: a 24-week, randomized, double-blind study. Clin Ther. 2010; 32:1234–1251.
crossref
14. Polinsky RJ. Clinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of Alzheimerʼs disease. Clin Ther. 1998; 20:634–647.
crossref
15. Cummings JL, Farlow MR, Meng X, Tekin S, Olin JT. Rivastigmine transdermal patch skin tolerability: results of a 1-year clinical trial in patients with mild-to-moderate Alzheimerʼs disease. Clin Drug Investig. 2010; 30:41–49.
16. Seltzer B. Galantamine-ER for the treatment of mild-to-moderate Alzheimerʼs disease. Clin Interv Aging. 2010; 5:1–6.
17. Wong CW. Pharmacotherapy for dementia: a practical approach to the use of cholinesterase inhibitors and memantine. Drugs Aging. 2016; 33:451–460.
crossref
18. Deschaintre Y, Richard F, Leys D, Pasquier F. Treatment of vascular risk factors is associated with slower decline in Alzheimer disease. Neurology. 2009; 73:674–680.
crossref
19. Kerchner GA, Tartaglia MC, Boxer A. Abhorring the vacuum: use of Alzheimerʼs disease medications in frontotemporal dementia. Expert Rev Neurother. 2011; 11:709–717.
crossref
20. Ngo J, Holroyd-Leduc JM. Systematic review of recent dementia practice guidelines. Age Ageing. 2015; 44:25–33.
crossref
21. Tricco AC, Soobiah C, Berliner S, Ho JM, Ng CH, Ashoor HM, Chen MH, Hemmelgarn B, Straus SE. Efficacy and safety of cognitive enhancers for patients with mild cognitive impairment: a systematic review and metaanalysis. CMAJ. 2013; 185:1393–1401.
crossref
22. Emre M. Switching cholinesterase inhibitors in patients with Alzheimerʼs disease. Int J Clin Pract Suppl. 2002; 127:64–72.
23. Rogawski MA, Wenk GL. The neuropharmacological basis for the use of memantine in the treatment of Alzheimerʼs disease. CNS Drug Rev. 2003; 9:275–308.
crossref
24. Schneider LS, Dagerman KS, Higgins JP, McShane R. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol. 2011; 68:991–998.
crossref
25. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004; 291:317–324.
26. Howard R, McShane R, Lindesay J, Ritchie C, Baldwin A, Barber R, Burns A, Dening T, Findlay D, Holmes C, Hughes A, Jacoby R, Jones R, Jones R, McKeith I, Macharouthu A, OʼBrien J, Passmore P, Sheehan B, Juszczak E, Katona C, Hills R, Knapp M, Ballard C, Brown R, Banerjee S, Onions C, Griffin M, Adams J, Gray R, Johnson T, Bentham P, Phillips P. Donepezil and memantine for moderate-to-severe Alzhei-merʼs disease. N Engl J Med. 2012; 366:893–903.
crossref
27. Wilkinson D. A review of the effects of memantine on clinical progression in Alzheimerʼs disease. Int J Geriatr Psychiatry. 2012; 27:769–776.
crossref
28. Azermai M, Petrovic M, Elseviers MM, Bourgeois J, Van Bortel LM, Vander Stichele RH. Systematic appraisal of dementia guidelines for the management of behavioural and psychological symptoms. Ageing Res Rev. 2012; 11:78–86.
crossref
29. Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a metaanalysis. JAMA. 2003; 289:210–216.
30. Azermai M. Dealing with behavioral and psychological symptoms of dementia: a general overview. Psychol Res Behav Manag. 2015; 8:181–185.
crossref
31. Wang F, Feng TY, Yang S, Preter M, Zhou JN, Wang XP. Drug therapy for behavioral and psychological symptoms of dementia. Curr Neuropharmacol. 2016; 14:307–313.
crossref
32. Katz IR, Jeste DV, Mintzer JE, Clyde C, Napolitano J, Brecher M. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group. J Clin Psychiatry. 1999; 60:107–115.
33. Bains J, Birks J, Dening T. Antidepressants for treating depression in dementia. Cochrane Database Syst Rev. 2002; 4:CD003944.
crossref
34. Tampi RR, Tampi DJ. Efficacy and tolerability of benzodia-zepines for the treatment of behavioral and psychological symptoms of dementia: a systematic review of randomized controlled trials. Am J Alzheimers Dis Other Demen. 2014; 29:565–574.
35. Pinheiro D. [Anticonvulsant mood stabilizers in the treatment of behavioral and psychological symptoms of dementia (BPSD)]. Encephale. 2008; 34:409–415.
36. Farina N, Llewellyn D, Isaac MG, Tabet N. Vitamin E for Alzheimerʼs dementia and mild cognitive impairment. Cochrane Database Syst Rev. 2017; 1:CD002854.
crossref
37. Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, Love S, Schellenberg GD, McCarten JR, Malphurs J, Prieto S, Chen P, Loreck DJ, Trapp G, Bakshi RS, Mintzer JE, Heidebrink JL, Vidal-Cardona A, Arroyo LM, Cruz AR, Zachariah S, Kowall NW, Chopra MP, Craft S, Thielke S, Turvey CL, Woodman C, Monnell KA, Gordon K, Tomaska J, Segal Y, Peduzzi PN, Guarino PD. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014; 311:33–44.
38. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2012; 3:CD007176.
crossref
39. Yuan Q, Wang CW, Shi J, Lin ZX. Effects of Ginkgo biloba on dementia: an overview of systematic reviews. J Ethnophar-macol. 2017; 195:1–9.
crossref
40. Scapicchio PL. Revisiting choline alphoscerate profile: a new, perspective, role in dementia? Int J Neurosci. 2013; 123:444–449.
crossref
41. Gavrilova SI, Kolykhalov IV, Ponomareva EV, Fedorova YB, Selezneva ND. Clinical efficacy and safety of choline alfoscerate in the treatment of late-onset cognitive impairment. Zh Nevrol Psikhiatr Im S S Korsakova. 2018; 118:45–53.
crossref
42. Burckhardt M, Herke M, Wustmann T, Watzke S, Langer G, Fink A. Omega-3 fatty acids for the treatment of dementia. Cochrane Database Syst Rev. 2016; 4:CD009002.
crossref
43. Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, Koss E, Pfeiffer E, Jin S, Gamst A, Grundman M, Thomas R, Thal LJ. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimerʼs Disease Cooperative Study. JAMA. 2000; 283:1007–1015.
44. Maki PM, Henderson VW. Hormone therapy, dementia, and cognition: the Womenʼs Health Initiative 10 years on. Climacteric. 2012; 15:256–262.
crossref
45. King DS, Wilburn AJ, Wofford MR, Harrell TK, Lindley BJ, Jones DW. Cognitive impairment associated with atorvastatin and simvastatin. Pharmacotherapy. 2003; 23:1663–1667.
crossref

Table 1.
Criteria for National Health Insurance coverage in Korea and dose recommendations for acetyl cholinesterase inhibitors and memantine for dementia treatment
  Donepezil High-dose donepezil Rivastigmine Rivastigmine (patch) Galantamine Memantine
Dose recommendation 5-10 mg 23 mg 6-12 mg 5-15 cm2 8-24 mg 5-20 mg
MMSE ≤26 ≤20 10-26 ≤26 10-26 ≤20
CDR 1-2 2-3 1-2 1-3 1-2 2-3
GDS 3-5 4-7 3-5 3-7 3-5 4-7

MMSE, Mini-Mental State Examination; CDR, Clinical Dementia Rating; GDS, Global Deterioration Scale.

Table 2.
General dose recommendations of medications for managing the behavioral and psychological symptoms of dementia
Recommended indication Medication General dose recommendation (mg)
Irritability, agitation, aggression Haloperidol 0.25-12
Risperidone 0.25-4
Quetiapine 25-600
Olanzapine 5-10
Aripiprazole 2-15
Oxcarbazepine 300-900
Fluvoxamine 25-200
Citalopram 10-40
Trazodone 50-300
Sertraline 25-200
Depression Escitalopram 5-15
Sertraline 25-150
Fluoxetine 10-40
TOOLS
Similar articles