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The Journal of Prevention of Alzheimer's Disease
Published in: The Journal of Prevention of Alzheimer's Disease 4/2021

Open Access 01-10-2021 | Risperidone | Original Research

Comparative Efficacy, Safety, Tolerability, and Effectiveness of Antipsychotics in The Treatment of Dementia-Related Psychosis (DRP): A Systematic Literature Review

Authors: I. Yunusa, N. Rashid, V. Abler, Krithika Rajagopalan

Published in: The Journal of Prevention of Alzheimer's Disease | Issue 4/2021

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Abstract

Objectives

To evaluate the comparative efficacy, safety, tolerability, and effectiveness of atypical antipsychotics (AAPs) for the treatment of dementia related psychosis (DRP) in older adults.

Methods

In this systematic literature review (SLR), we qualitatively synthesized evidence on the comparative efficacy (based on neuropsychiatric inventory), tolerability (weight gain), and safety (cerebrovascular adverse events [CVAE], cardiovascular events, mortality, somnolence, extrapyramidal symptoms [EPS]) of AAPs used to treat DRP. We also assessed effectiveness based on all-cause discontinuations and discontinuations due to lack of efficacy or adverse events (AE). Published articles from through March 2021 from PubMed, EMBASE, PsycINFO, and Cochrane databases evaluated. We included double-blind, active-comparator/placebo-controlled randomized trials, open-label trials, and observational studies.

Results

This qualitative synthesis included 51 eligible studies with sample size of 13,334 and mean age of 79.36 years. Risperidone, olanzapine, quetiapine, and aripiprazole demonstrated numerically small improvement in psychotic symptoms among patients with DRP. Somnolence was the most reported AE for all the AAPs, with weight gain and tardive dyskinesia more common with olanzapine and risperidone, respectively. These AAPs are associated with falls, EPS, cognitive declines, CVAE, and mortality. Aripiprazole and olanzapine had lower odds of discontinuation due to lack of efficacy, with olanzapine having greater discontinuation odds due to AEs.

Conclusion

This SLR demonstrated that AAPs used off-label to treat DRP are associated with small numerical symptom improvement but with a high risk of AEs, including cognitive decline and potentially higher mortality. These results underscore the need for new treatments with a favorable benefit-risk profile for treating DRP.
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Literature
1.
2.
Prince M, Ali GC, Guerchet M, Prina AM, Albanese E, Wu YT. Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimers Res Ther. 2016;8(1):23.PubMedPubMedCentralCrossRef
3.
Sink KM, Holden KF, Yaffe K. Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. Jama. 2005;293(5):596–608.PubMedCrossRef
4.
Kales HC, Gitlin LN, Lyketsos CG, Detroit Expert Panel on A, Management of Neuropsychiatric Symptoms of D. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatr Soc. 2014;62(4):762–769.PubMedPubMedCentralCrossRef
5.
Small GW. Managing the Burden of Dementia-Related Delusions and Hallucinations. Supplement to The Journal of Family Practice. 69(7).
6.
Paulsen JS, Salmon DP, Thal LJ, et al. Incidence of and risk factors for hallucinations and delusions in patients with probable AD. Neurology. 2000;54(10):1965–1971.PubMedCrossRef
7.
Wilson RS, Gilley DW, Bennett DA, Beckett LA, Evans DA. Hallucinations, delusions, and cognitive decline in Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2000;69(2):172–177.PubMedPubMedCentralCrossRef
8.
Scarmeas N, Brandt J, Albert M, et al. Delusions and Hallucinations Are Associated With Worse Outcome in Alzheimer Disease. Archives of Neurology. 2005;62(10):1601–1608.PubMedPubMedCentralCrossRef
9.
Maust DT, Kim HM, Seyfried LS, et al. Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiatry. 2015;72(5):438–445.PubMedPubMedCentralCrossRef
10.
Hsu WT, Esmaily-Fard A, Lai CC, et al. Antipsychotics and the Risk of Cerebrovascular Accident: A Systematic Review and Meta-Analysis of Observational Studies. J Am Med Dir Assoc. 2017;18(8):692–699.PubMedCrossRef
11.
Mittal V, Kurup L, Williamson D, Muralee S, Tampi RR. Risk of cerebrovascular adverse events and death in elderly patients with dementia when treated with antipsychotic medications: a literature review of evidence. Am J Alzheimers Dis Other Demen. 2011;26(1):10–28.PubMedCrossRef
12.
Citrome L, Eramo A, Francois C, et al. Lack of tolerable treatment options for patients with schizophrenia. Neuropsychiatric disease and treatment. 2015;11:3095.PubMedPubMedCentralCrossRef
13.
Papola D, Ostuzzi G, Thabane L, Guyatt G, Barbui C. Antipsychotic drug exposure and risk of fracture: a systematic review and meta-analysis of observational studies. Int Clin Psychopharmacol. 2018;33(4):181–196.PubMedCrossRef
14.
Reus VI, Fochtmann LJ, Eyler AE, et al. The American Psychiatric Association Practice Guideline on the Use of Antipsychotics to Treat Agitation or Psychosis in Patients With Dementia. Focus (Am Psychiatr Publ). 2017;15(1):81–84.
15.
Yunusa I, Alsumali A, Garba AE, Regestein QR, Eguale T. Assessment of Reported Comparative Effectiveness and Safety of Atypical Antipsychotics in the Treatment of Behavioral and Psychological Symptoms of Dementia: A Network Meta-analysis. JAMA Netw Open. 2019;2(3):e190828.PubMedPubMedCentralCrossRef
16.
Watt JA, Goodarzi Z, Veroniki AA, et al. Safety of pharmacologic interventions for neuropsychiatric symptoms in dementia: a systematic review and network meta-analysis. BMC Geriatr. 2020;20(1):212.PubMedPubMedCentralCrossRef
17.
Grossberg GT, Kohegyi E, Mergel V, et al. Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer’s dementia: two 12-week, randomized, double-blind, placebo-controlled trials. The American Journal of Geriatric Psychiatry. 2020;28(4):383–400.PubMedCrossRef
18.
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Int J Surg. 2021:105906.
19.
20.
Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Non-Randomized Studies in Meta-Analysis. 2000
21.
Ballard C, Lana MM, Theodoulou M, et al. A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial). PLoS Med. 2008;5(4):e76.PubMedPubMedCentralCrossRef
22.
Ballard C, Margallo-Lana M, Juszczak E, et al. Quetiapine and rivastigmine and cognitive decline in Alzheimer’s disease: randomised double blind placebo controlled trial. Bmj. 2005;330(7496):874.PubMedPubMedCentralCrossRef
23.
Barak Y, Plopski I, Tadger S, Paleacu D. Escitalopram versus risperidone for the treatment of behavioral and psychotic symptoms associated with Alzheimer’s disease: a randomized double-blind pilot study. International psychogeriatrics. 2011;23(9):1515–1519.PubMedCrossRef
24.
Brodaty H, Ames D, Snowdon J, et al. Risperidone for psychosis of Alzheimer’s disease and mixed dementia: results of a double-blind, placebo-controlled trial. International Journal of Geriatric Psychiatry: A journal of the psychiatry of late life and allied sciences. 2005;20(12):1153–1157.CrossRef
25.
Brodaty H, Ames D, Snowdon J, et al. A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia. The Journal of clinical psychiatry. 2003.
26.
Chan Wc, Lam LCw, Choy CNp, Leung VPy, Li Sw, Chiu HFk. A double-blind randomised comparison of risperidone and haloperidol in the treatment of behavioural and psychological symptoms in Chinese dementia patients. International journal of geriatric psychiatry. 2001;16(12):1156–1162.PubMedCrossRef
27.
Clark WS, Street JS, Feldman PD, Breier A. The effects of olanzapine in reducing the emergence of psychosis among nursing home patients with Alzheimer’s disease. The Journal of clinical psychiatry. 2001.
28.
Culo S, Mulsant BH, Rosen J, et al. Treating neuropsychiatric symptoms in dementia with Lewy bodies: a randomized controlled-trial. Alzheimer Disease & Associated Disorders. 2010;24(4):360–364.CrossRef
29.
Cummings JL, Street J, Masterman D, Clark WS. Efficacy of olanzapine in the treatment of psychosis in dementia with Lewy bodies. Dementia and geriatric cognitive disorders. 2002;13(2):67–73.PubMedCrossRef
30.
De Deyn P, Jeste DV, Swanink R, et al. Aripiprazole for the treatment of psychosis in patients with Alzheimer’s disease: a randomized, placebo-controlled study. Journal of clinical psychopharmacology. 2005;25(5):463–467.PubMedCrossRef
31.
De Deyn PP, Carrasco MM, Deberdt W, et al. Olanzapine versus placebo in the treatment of psychosis with or without associated behavioral disturbances in patients with Alzheimer’s disease. International journal of geriatric psychiatry. 2004;19(2):115–126.PubMedCrossRef
32.
De Deyn PP, Eriksson H, Svensson H. Tolerability of extended-release quetiapine fumarate compared with immediate-release quetiapine fumarate in older patients with Alzheimer’s disease with symptoms of psychosis and/or agitation: a randomised, double-blind, parallel-group study. Int J Geriatr Psychiatry. 2012;27(3):296–304.PubMedCrossRef
33.
Deberdt WG, Dysken MW, Rappaport SA, et al. Comparison of olanzapine and risperidone in the treatment of psychosis and associated behavioral disturbances in patients with dementia. The American journal of geriatric psychiatry. 2005;13(8):722–730.PubMedCrossRef
34.
Devanand D, Mintzer J, Schultz SK, et al. Relapse risk after discontinuation of risperidone in Alzheimer’s disease. New England Journal of Medicine. 2012;367(16):1497–1507.CrossRefPubMed
35.
Ellingrod VL, Schultz SK, Ekstam-Smith K, Kutscher E, Turvey C, Arndt S. Comparison of risperidone with olanzapine in elderly patients with dementia and psychosis. Pharmacotherapy. 2002;22(1):1–5.PubMedCrossRef
36.
Freund-Levi Y, Jedenius E, Tysen-Bäckström AC, Lärksäter M, Wahlund L-O, Eriksdotter M. Galantamine versus risperidone treatment of neuropsychiatric symptoms in patients with probable dementia: an open randomized trial. The American journal of geriatric psychiatry. 2014;22(4):341–348.PubMedCrossRef
37.
Fujikawa T, Takahashi T, Kinoshita A, et al. Quetiapine treatment for behavioral and psychological symptoms in patients with senile dementia of Alzheimer type. Neuropsychobiology. 2004;49(4):201–204.PubMedCrossRef
38.
Gareri P, Cotroneo A, Lacava R, et al. Comparison of the efficacy of new and conventional antipsychotic drugs in the treatment of behavioral and psychological symptoms of dementia (BPSD). Archives of gerontology and geriatrics Supplement. 2004(9):207.
39.
Holmes C, Wilkinson D, Dean C, et al. Risperidone and rivastigmine and agitated behaviour in severe Alzheimer’s disease: a randomised double blind placebo controlled study. Int J Geriatr Psychiatry. 2007;22(4):380–381.PubMedCrossRef
40.
Jeste DV, Okamoto A, Napolitano J, Kane JM, Martinez RA. Low incidence of persistent tardive dyskinesia in elderly patients with dementia treated with risperidone. American Journal of Psychiatry. 2000;157(7):1150–1155.CrossRefPubMed
41.
Kurlan R, Cummings J, Raman R, Thal L. Quetiapine for agitation or psychosis in patients with dementia and parkinsonism. Neurology. 2007;68(17):1356–1363.PubMedCrossRef
42.
Kurz A, Schwalen S, Schmitt A. Effects of risperidone on behavioral and psychological symptoms associated with dementia in clinical practice. International psychogeriatrics. 2005;17(4):605.PubMedCrossRef
43.
Laks J, Engelhardt E, Marinho V, et al. Efficacy and safety of risperidone oral solution in agitation associated with dementia in the elderly. Arquivos de neuro-psiquiatria. 2001;59(4):859–864.PubMedCrossRef
44.
Lim H-K, Pae C-U, Lee C, Lee C-U. Amisulpride versus risperidone treatment for behavioral and psychological symptoms in patients with dementia of the Alzheimer type: a randomized, open, prospective study. Neuropsychobiology. 2006;54(4):247–251.PubMedCrossRef
45.
Mintzer J, Greenspan A, Caers I, et al. Risperidone in the treatment of psychosis of Alzheimer disease: results from a prospective clinical trial. The American journal of geriatric psychiatry. 2006;14(3):280–291.PubMedCrossRef
46.
Mintzer JE, Tune LE, Breder CD, et al. Aripiprazole for the treatment of psychoses in institutionalized patients with Alzheimer dementia: a multicenter, randomized, double-blind, placebo-controlled assessment of three fixed doses. The American Journal of Geriatric Psychiatry. 2007;15(11):918–931.PubMedCrossRef
47.
Mullen J, Jibson MD, Sweitzer D. A comparison of the relative safety, efficacy, and tolerability of quetiapine and risperidone in outpatients with schizophrenia and other psychotic disorders: the quetiapine experience with safety and tolerability (QUEST) study. Clin Ther. 2001;23(11):1839–1854.PubMedCrossRef
48.
Onor ML, Saina M, Aguglia E. Efficacy and tolerability of quetiapine in the treatment of behavioral and psychological symptoms of dementia. American Journal of Alzheimer’s Disease & Other Dementias®. 2007;21(6):448–453.CrossRef
49.
Paleacu D, Barak Y, Mirecky I, Mazeh D. Quetiapine treatment for behavioural and psychological symptoms of dementia in Alzheimer’s disease patients: a 6-week, double-blind, placebo-controlled study. International Journal of Geriatric Psychiatry: A journal of the psychiatry of late life and allied sciences. 2008;23(4):393–400.CrossRef
50.
Pollock BG, Mulsant BH, Rosen J, et al. A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. The American Journal of Geriatric Psychiatry. 2007;15(11):942–952.PubMedCrossRef
51.
Rabinowitz J, Katz I, De Deyn PP, Greenspan A, Brodaty H. Treating behavioral and psychological symptoms in patients with psychosis of Alzheimer’s disease using risperidone. International psychogeriatrics. 2007;19(2):227–240.PubMedCrossRef
52.
Rainer M, Haushofer M, Pfolz H, Struhal C, Wick W. Quetiapine versus risperidone in elderly patients with behavioural and psychological symptoms of dementia: efficacy, safety and cognitive function. European psychiatry. 2007;22(6):395–403.PubMedCrossRef
53.
Rocha FL, Hara C, Ramos MG, et al. An exploratory open-label trial of ziprasidone for the treatment of behavioral and psychological symptoms of dementia. Dementia and geriatric cognitive disorders. 2006;22(5–6):445–448.PubMedCrossRef
54.
Ruths S, Straand J, Nygaard HA, Bjorvatn B, Pallesen S. Effect of antipsychotic withdrawal on behavior and sleep/wake activity in nursing home residents with dementia: a randomized, placebo-controlled, double-blinded study The Bergen District Nursing Home Study. J Am Geriatr Soc. 2004;52(10):1737–1743.PubMedCrossRef
55.
Scharre DW, Chang S-I. Cognitive and behavioral effects of quetiapine in Alzheimer disease patients. Alzheimer Disease & Associated Disorders. 2002;16(2):128–130.CrossRef
56.
Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. New England Journal of Medicine. 2006;355(15):1525–1538.CrossRefPubMed
57.
Street JS, Clark WS, Gannon KS, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. Archives of General Psychiatry. 2000;57(10):968–976.PubMedCrossRef
58.
Streim JE, Porsteinsson AP, Breder CD, et al. A randomized, double-blind, placebo-controlled study of aripiprazole for the treatment of psychosis in nursing home patients with Alzheimer disease. The American Journal of Geriatric Psychiatry. 2008;16(7):537–550.PubMedCrossRef
59.
Suh GH, Greenspan AJ, Choi SK. Comparative efficacy of risperidone versus haloperidol on behavioural and psychological symptoms of dementia. International Journal of Geriatric Psychiatry: A journal of the psychiatry of late life and allied sciences. 2006;21(7):654–660.CrossRef
60.
Sultzer DL, Davis SM, Tariot PN, et al. Clinical symptom responses to atypical antipsychotic medications in Alzheimer’s disease: phase 1 outcomes from the CATIE-AD effectiveness trial. American Journal of Psychiatry. 2008;165(7):844–854.CrossRefPubMed
61.
Tariot PN, Salzman C, Yeung PP, Pute J, Rak IW. Long-term use of quetiapine in elderly patients with psychotic disorders. Clinical Therapeutics. 2000;22(9):1068–1084.PubMedCrossRef
62.
Tariot PN, Schneider L, Katz IR, et al. Quetiapine treatment of psychosis associated with dementia: a double-blind, randomized, placebo-controlled clinical trial. The American journal of geriatric psychiatry. 2006;14(9):767–776.PubMedCrossRef
63.
Teranishi M, Kurita M, Nishino S, et al. Efficacy and tolerability of risperidone, yokukansan, and fluvoxamine for the treatment of behavioral and psychological symptoms of dementia: a blinded, randomized trial. Journal of clinical psychopharmacology. 2013;33(5):600–607.PubMedCrossRef
64.
Verhey FR, Verkaaik M, Lousberg R. Olanzapine versus haloperidol in the treatment of agitation in elderly patients with dementia: results of a randomized controlled double-blind trial. Dementia and geriatric cognitive disorders. 2006;21(1):1–8.PubMedCrossRef
65.
Vigen CL, Mack WJ, Keefe RS, et al. Cognitive effects of atypical antipsychotic medications in patients with Alzheimer’s disease: outcomes from CATIE-AD. American Journal of Psychiatry. 2011;168(8):831–839.CrossRefPubMed
66.
Yang X-P, Wang Y-T, Liu D-C, et al. Comparison of the effects of tiapride and risperidone on psycho-behavioral symptoms of senile dementia. Int J Clin Exp Med. 2016;9(6):9593–9597.
67.
Yoon JS, Kim JM, Lee H, Shin IS, Choi SK. Risperidone use in Korean patients with Alzheimer’s disease: optimal dosage and effect on behavioural and psychological symptoms, cognitive function and activities of daily living. Human Psychopharmacology: Clinical and Experimental. 2003;18(8):627–633.CrossRef
68.
Zhong KX, Tariot P, Mintzer J, Minkwitz M, Devine N. Quetiapine to treat agitation in dementia: a randomized, double-blind, placebo-controlled study. Current Alzheimer Research. 2007;4(1):81–93.PubMedCrossRef
69.
Mintzer J, Faison W, Street JS, Sutton VK, Breier A. Olanzapine in the treatment of anxiety symptoms due to Alzheimer’s disease: a post hoc analysis. International journal of geriatric psychiatry. 2001;16(S1):S71–S77.PubMedCrossRef
70.
Mulsant BH, Gharabawi GM, Bossie CA, et al. Correlates of anticholinergic activity in patients with dementia and psychosis treated with risperidone or olanzapine. J Clin Psychiatry. 2004;65(12):1708–1714.PubMedCrossRef
71.
Rainer MK, Masching AJ, Ertl MG, Kraxberger E, Haushofer M. Effect of risperidone on behavioral and psychological symptoms and cognitive function in dementia. J Clin Psychiatry. 2001;62(11):894–900.PubMedCrossRef
72.
Savaskan E, Schnitzler C, Schröder C, Cajochen C, Müller-Spahn F, Wirz-Justice A. Treatment of behavioural, cognitive and circadian rest-activity cycle disturbances in Alzheimer’s disease: haloperidol vs. quetiapine. Int J Neuropsychopharmacol. 2006;9(5):507–516.PubMedCrossRef
73.
Weiser M, Rotmensch HH, Korczyn AD, Hartman R, Cicin-Sain A, Anand R. A pilot, randomized, open-label trial assessing safety and pharmakokinetic parameters of co-administration of rivastigmine with risperidone in dementia patients with behavioral disturbances. Int J Geriatr Psychiatry. 2002;17(4):343–346.PubMedCrossRef
74.
Mowla A, Pani A. Comparison of topiramate and risperidone for the treatment of behavioral disturbances of patients with Alzheimer disease: a double-blind, randomized clinical trial. J Clin Psychopharmacol. 2010;30(1):40–43.PubMedCrossRef
75.
Ruths S, Straand J, Nygaard HA, Aarsland D. Stopping antipsychotic drug therapy in demented nursing home patients: a randomized, placebo-controlled study—the Bergen District Nursing Home Study (BEDNURS). Int J Geriatr Psychiatry. 2008;23(9):889–895.PubMedCrossRef
76.
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(2):107–115.PubMedCrossRef
77.
Kinon BJ, Stauffer VL, McGuire HC, Kaiser CJ, Dickson RA, Kennedy JS. The effects of antipsychotic drug treatment on prolactin concentrations in elderly patients. J Am Med Dir Assoc. 2003;4(4):189–194.PubMedCrossRef
78.
79.
Corbett A, Burns A, Ballard C. Don’t use antipsychotics routinely to treat agitation and aggression in people with dementia. BMJ. 2014;349:g6420.PubMedCrossRef
80.
Papola D, Ostuzzi G, Gastaldon C, et al. Antipsychotic use and risk of life-threatening medical events: umbrella review of observational studies. Acta Psychiatr Scand. 2019;140(3):227–243.PubMedCrossRef
81.
Ballard C, Howard R. Neuroleptic drugs in dementia: benefits and harm. Nat Rev Neurosci. 2006;7(6):492–500.PubMedCrossRef
Metadata
Title
Comparative Efficacy, Safety, Tolerability, and Effectiveness of Antipsychotics in The Treatment of Dementia-Related Psychosis (DRP): A Systematic Literature Review
Authors
I. Yunusa
N. Rashid
V. Abler
Krithika Rajagopalan
Publication date
01-10-2021

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