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. 2021 Dec 17;12(12):CD013304.
doi: 10.1002/14651858.CD013304.pub2.

Antipsychotics for agitation and psychosis in people with Alzheimer's disease and vascular dementia

Viktoria Mühlbauer  1 , Ralph Möhler  2 , Martin N Dichter  3 , Sytse U Zuidema  4 , Sascha Köpke  5 , Hendrika J Luijendijk  4
Affiliations

Antipsychotics for agitation and psychosis in people with Alzheimer's disease and vascular dementia

Viktoria Mühlbauer et al. Cochrane Database Syst Rev. .

Abstract

Background: Typical and atypical antipsychotics are widely used to treat agitation and psychosis in dementia. However, whether or not they are beneficial is uncertain. Some trials have yielded negative results and effectiveness may be outweighed by harms.

Objectives: To assess the efficacy and safety of antipsychotics for the treatment of agitation and psychosis in people with Alzheimer's disease and vascular dementia.

Search methods: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE (Ovid Sp), Embase (Ovid SP), PsycINFO (Ovid SP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), ClinicalTrials.gov and the World Health Organization's meta-register, and the International Clinical Trials Registry Portal on 7 January 2021. Two review authors independently screened the title and abstract of the hits, and two review authors assessed the full text of studies that got through this screening.

Selection criteria: We included randomised, placebo-controlled, parallel-arm trials comparing the effects of antipsychotics and placebo for the treatment of agitation or psychosis in people with dementia due to Alzheimer's disease or vascular dementia, or both, irrespective of age, severity of cognitive impairment, and setting. (The majority of) participants had to have clinically significant agitation (including aggression) or psychosis or both at baseline. We excluded studies about antipsychotics that are no longer available in the USA or EU, or that are used for emergency short-term sedation. We also excluded head-to-head trials and antipsychotic withdrawal trials.

Data collection and analysis: The primary outcomes were (1) reduction in agitation or psychosis in participants with agitation or psychosis, respectively at baseline, and (2) the number of participants with adverse events: somnolence, extrapyramidal symptoms, any adverse event, any serious adverse event (SAE), and death. Two review authors independently extracted the necessary data and assessed risk of bias with the Cochrane risk of bias tool. We calculated the pooled effect on agitation and psychosis for typical and atypical antipsychotics separately, and the pooled risk of adverse effects independent of the target symptom (agitation or psychosis). We used RevMan Web for the analyses.

Main results: The search yielded 8233 separate hits. After assessing the full-text of 35 studies, we included 24 trials that met the eligibility criteria. Six trials tested a typical antipsychotic, four for agitation and two for psychosis. Twenty trials tested an atypical antipsychotic, eight for agitation and 12 for psychosis. Two trials tested both drug types. Seventeen of 26 comparisons were performed in patients with Alzheimer's disease specifically. The other nine comparisons also included patients with vascular dementia or mixed dementia. Together, the studies included 6090 participants (12 to 652 per study). The trials were performed in institutionalised, hospitalised and community-dwelling patients, or a combination of those. For typical antipsychotics (e.g. haloperidol, thiothixene), we are uncertain whether these drugs improve agitation compared with placebo (standardised mean difference (SMD) -0.36, 95% confidence interval (CI) -0.57 to -0.15, 4 studies, n = 361); very low-certainty evidence, but typical antipsychotics may improve psychosis slightly (SMD -0.29, 95% CI -0.55 to -0.03, 2studies, n= 240; low-certainty evidence) compared with placebo. These drugs probably increase the risk of somnolence (risk ratio (RR) 2.62, 95% CI 1.51 to 4.56, 3 studies, n = 466; moderate-certainty evidence) and increase extrapyramidal symptoms (RR 2.26, 95% CI 1.58 to 3.23, 3 studies, n = 467; high-certainty) evidence. There was no evidence regarding the risk of any adverse event. The risks of SAEs (RR 1.32, 95% CI 0.65 to 2.66, 1 study, n = 193) and death (RR 1.46, 95% CI 0.54 to 4.00, 6 studies, n = 578) may be increased slightly, but these estimates were very imprecise, and the certainty was low. The effect estimates for haloperidol from five trials were in line with those of the drug class. Atypical antipsychotics (e.g. risperidone, olanzapine, aripiprazole, quetiapine) probably reduce agitation slightly (SMD -0.21, 95% CI -0.30 to -0.12, 7 studies, n = 1971; moderate-certainty evidence), but probably have a negligible effect on psychosis (SMD -0.11, 95% CI -0.18 to -0.03, 12 studies, n = 3364; moderate-certainty evidence). These drugs increase the risk of somnolence (RR 1.93, 95% CI 1.57 to 2.39, 13 studies, n - 3878; high-certainty evidence) and are probably also associated with slightly increased risk of extrapyramidal symptoms (RR 1.39, 95% CI 1.14 to 1.68, 15 studies, n = 4180; moderate-certainty evidence), serious adverse events (RR 1.32, 95% CI 1.09 to 1.61, 15 studies, n= 4316; moderate-certainty evidence) and death (RR 1.36, 95% CI 0.90 to 2.05, 17 studies, n= 5032; moderate-certainty evidence), although the latter estimate was imprecise. The drugs probably have a negligible effect on the risk of any adverse event (RR 1.05, 95% CI 1.02 to 1.09, 11 studies, n = 2785; moderate-certainty evidence). The findings from seven trials for risperidone were in line with those for the drug class.

Authors' conclusions: There is some evidence that typical antipsychotics might decrease agitation and psychosis slightly in patients with dementia. Atypical antipsychotics reduce agitation in dementia slightly, but their effect on psychosis in dementia is negligible. The apparent effectiveness of the drugs seen in daily practice may be explained by a favourable natural course of the symptoms, as observed in the placebo groups. Both drug classes increase the risk of somnolence and other adverse events. If antipsychotics are considered for sedation in patients with severe and dangerous symptoms, this should be discussed openly with the patient and legal representative.

Trial registration: ClinicalTrials.gov NCT02035553 NCT00036114.

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Conflict of interest statement

VM: none known

RM: none known

MND: none known

SUZ: none known

SK: none known

HJL: none known

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary
3
3
Risk of bias graph
4
4
Funnel plot: Analysis 3.2 (Psychosis, atypical antipsychotics)
5
5
Funnel plot: Analysis 3.3 (Somnolence, atypical antipsychotics)
6
6
Funnel plot: Analysis 3.5 (Extrapyramidal symptoms, atypical antipsychotics)
7
7
Funnel plot: Analysis 3.7 (Any adverse event, atypical antipsychotics)
8
8
Funnel plot: Analysis 3.9 (Any serious adverse event, atypical antipsychotics)
9
9
Funnel plot: Analysis 3.11 (Death, atypical antipsychotics)
10
10
Funnel plot: Analysis 3.17 (Discontinuation due to adverse events, atypical antipsychotics)
11
11
Funnel plot: Analysis 3.19 (Discontinuation (any reason), atypical antipsychotics)
12
12
Funnel plot: Analysis 3.22 (Cognitive function, atypical antipsychotics)
13
13
Forest plot (1.1 Agitation)
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14
Forest plot (1.2 Psychosis)
15
15
Forest plot (1.3 Somnolence)
16
16
Forest plot (1.5 Extrapyramidal symptoms)
17
17
Forest plot (1.9 Death)
18
18
Forest plot (1.11 Number of responders for agitation)
19
19
Forest plot (1.13 Number of responders for psychosis)
20
20
Forest plot (1.15 Discontinuation due to adverse events)
21
21
Forest plot (1.17 Discontinuation, any reason)
22
22
Forest plot (1.19 Functioning (ADL))
23
23
Forest plot (1.20 Cognitive function)
24
24
Forest plot (2.1 Agitation)
25
25
Forest plot (2.2 Psychosis)
26
26
Forest plot (2.3 Somnolence)
27
27
Forest plot (2.6 Death)
28
28
Forest plot (2.7 Number of responders for agitation)
29
29
Forest plot (2.8 Number of responders for psychosis)
30
30
Forest plot (2.9 Discontinuation due to adverse events)
31
31
Forest plot (2.10 Discontinuation, any reason)
32
32
Forest plot (2.11 Functioning (ADL))
33
33
Forest plot (2.12 Cognitive function)
34
34
Forest plot (3.1 Agitation)
35
35
Forest plot (3.2 Psychosis)
36
36
Forest plot (3.3 Somnolence)
37
37
Forest plot (3.5 Extrapyramidal symptoms)
38
38
Forest plot (3.7 Any adverse event)
39
39
Forest plot (3.9 Any serious adverse event)
40
40
Forest plot (3.11 Death)
41
41
Forest plot (3.13 Number of responders for agitation)
42
42
Forest plot (3.15 Number of responders for psychosis)
43
43
Forest plot (3.17 Discontinuation due to adverse events)
44
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Forest plot (3.19 Discontinuation, any reason)
45
45
Forest plot (3.21 Functioning (ADL))
46
46
Forest plot (3.22 Cognitive function)
47
47
Forest plot (4.1 Agitation)
48
48
Forest plot (4.2 Psychosis)
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49
Forest plot (4.3 Somnolence)
50
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Forest plot (4.4 Extrapyramidal symptoms)
51
51
Forest plot (4.5 Any adverse event)
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52
Forest plot (4.6 Any serious adverse event)
53
53
Forest plot (4.7 Death)
54
54
Forest plot (4.8 Number of responders for agitation)
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55
Forest plot (4.9 Number of responders for psychosis)
56
56
Forest plot (4.10 Discontinuation due to adverse events)
57
57
Forest plot (4.11 Discontinuation, any reason)
58
58
Forest plot (4.12 Cognitive function)
59
59
Forest plot (5.1 Agitation)
60
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Forest plot (5.2 Psychosis)
61
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Forest plot (5.3 Somnolence)
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Forest plot (5.4 Extrapyramidal symptoms)
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Forest plot (5.5 Any adverse event)
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Forest plot (5.6 Any serious adverse event)
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Forest plot (5.7 Death)
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Forest plot (5.8 Number of responders for agitation)
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Forest plot (5.9 Number of responders for psychosis)
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Forest plot (5.10 Discontinuation due to adverse events)
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Forest plot (5.11 Discontinuation, any reason)
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Forest plot (5.12 Functioning (ADL))
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71
Forest plot (5.13 Cognitive function)
1.1
1.1. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 1: Agitation
1.2
1.2. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 2: Psychosis
1.3
1.3. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 3: Somnolence
1.4
1.4. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 4: Somnolence (RD)
1.5
1.5. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 5: Extrapyramidal symptoms
1.6
1.6. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 6: Extrapyramidal symptoms (RD)
1.7
1.7. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 7: Any serious adverse events
1.8
1.8. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 8: Any serious adverse events (RD)
1.9
1.9. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 9: Death
1.10
1.10. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 10: Death (RD)
1.11
1.11. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 11: Number of responders for agitation
1.12
1.12. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 12: Number of responders for agitation (RD)
1.13
1.13. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 13: Number of responders for psychosis
1.14
1.14. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 14: Number of responders for psychosis (RD)
1.15
1.15. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 15: Discontinuation due to adverse events
1.16
1.16. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 16: Discontinuation due to adverse events (RD)
1.17
1.17. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 17: Discontinuation (any reason)
1.18
1.18. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 18: Discontinuation (any reason) (RD)
1.19
1.19. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 19: Functioning (ADL)
1.20
1.20. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 20: Cognitive function
1.21
1.21. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 21: Carer burden
2.1
2.1. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 1: Agitation
2.2
2.2. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 2: Psychosis
2.3
2.3. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 3: Somnolence
2.4
2.4. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 4: Extrapyramidal symptoms
2.5
2.5. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 5: Serious adverse events
2.6
2.6. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 6: Death
2.7
2.7. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 7: Number of responders for agitation
2.8
2.8. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 8: Number of responders for psychosis
2.9
2.9. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 9: Discontinuation due to adverse events
2.10
2.10. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 10: Discontinuation (any reason)
2.11
2.11. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 11: Functioning (ADL)
2.12
2.12. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 12: Cognitive function
2.13
2.13. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 13: Carer burden
3.1
3.1. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 1: Agitation
3.2
3.2. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 2: Psychosis
3.3
3.3. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 3: Somnolence
3.4
3.4. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 4: Somnolence (RD)
3.5
3.5. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 5: Extrapyramidal symptoms
3.6
3.6. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 6: Extrapyramidal symptoms (RD)
3.7
3.7. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 7: Any adverse event
3.8
3.8. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 8: Any adverse event (RD)
3.9
3.9. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 9: Any serious adverse event
3.10
3.10. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 10: Any serious adverse event (RD)
3.11
3.11. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 11: Death
3.12
3.12. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 12: Death (RD)
3.13
3.13. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 13: Number of responders for agitation
3.14
3.14. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 14: Number of responders for agitation (RD)
3.15
3.15. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 15: Number of responders for psychosis
3.16
3.16. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 16: Number of responders for psychosis (RD)
3.17
3.17. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 17: Discontinuation due to adverse events
3.18
3.18. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 18: Discontinuation due to adverse events (RD)
3.19
3.19. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 19: Discontinuation (any reason)
3.20
3.20. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 20: Discontinuation (any reason) (RD)
3.21
3.21. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 21: Functioning (ADL)
3.22
3.22. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 22: Cognitive function
3.23
3.23. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 23: Cognitive function (single study)
3.24
3.24. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 24: Health‐related quality of life
3.25
3.25. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 25: Time spend providing care (caregiver)
4.1
4.1. Analysis
Comparison 4: Risperidone versus placebo, Outcome 1: Agitation
4.2
4.2. Analysis
Comparison 4: Risperidone versus placebo, Outcome 2: Psychosis
4.3
4.3. Analysis
Comparison 4: Risperidone versus placebo, Outcome 3: Somnolence
4.4
4.4. Analysis
Comparison 4: Risperidone versus placebo, Outcome 4: Extrapyramidal symptoms
4.5
4.5. Analysis
Comparison 4: Risperidone versus placebo, Outcome 5: Any adverse event
4.6
4.6. Analysis
Comparison 4: Risperidone versus placebo, Outcome 6: Any serious adverse event
4.7
4.7. Analysis
Comparison 4: Risperidone versus placebo, Outcome 7: Death
4.8
4.8. Analysis
Comparison 4: Risperidone versus placebo, Outcome 8: Number of responders for agitation
4.9
4.9. Analysis
Comparison 4: Risperidone versus placebo, Outcome 9: Number of responders for psychosis
4.10
4.10. Analysis
Comparison 4: Risperidone versus placebo, Outcome 10: Discontinuation due to adverse events
4.11
4.11. Analysis
Comparison 4: Risperidone versus placebo, Outcome 11: Discontinuation (any reason)
4.12
4.12. Analysis
Comparison 4: Risperidone versus placebo, Outcome 12: Cognitive function
4.13
4.13. Analysis
Comparison 4: Risperidone versus placebo, Outcome 13: Functioning (ADL)
4.14
4.14. Analysis
Comparison 4: Risperidone versus placebo, Outcome 14: Health‐related quality of life
4.15
4.15. Analysis
Comparison 4: Risperidone versus placebo, Outcome 15: Time spend providing care (caregiver)
5.1
5.1. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 1: Agitation
5.2
5.2. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 2: Psychosis
5.3
5.3. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 3: Somnolence
5.4
5.4. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 4: Extrapyramidal symptoms
5.5
5.5. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 5: Any adverse event
5.6
5.6. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 6: Any serious adverse event
5.7
5.7. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 7: Death
5.8
5.8. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 8: Number of responders for agitation
5.9
5.9. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 9: Number of responders for psychosis
5.10
5.10. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 10: Discontinuation due to adverse events
5.11
5.11. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 11: Discontinuation (any reason)
5.12
5.12. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 12: Functioning (ADL)
5.13
5.13. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 13: Cognitive function
5.14
5.14. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 14: Cognitive function (single study)
5.15
5.15. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 15: Health‐related quality of life
5.16
5.16. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 16: Time spend providing care (caregiver)
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Update of

  • doi: 10.1002/14651858.CD013304

References

References to studies included in this review

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Grossberg 2020b {published data only}
    1. Grossberg GT, Kohegyi E, Mergel V, Josiassen MK, Meulien D, Hobart M, et al. Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer's Dementia: two12-week, randomized, double-blind, placebo-controlled trials. American Journal of Geriatric Psychiatry 2020;28(4):383-400. - PubMed
Japic CTI 142578 2015 {published data only}
    1. JapicCTI-142578. Aripiprazole for the treatment of patients with agitation associated with dementia of the Alzheimer's type. http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-14... 2015.
Mintzer 2006 RIS USA 232 {published data only}
    1. Colon S, Figueroa C, Thein S, Siegal A, Arias B, De La Ganadara J, et al. Efficacy and safety of a flexible dose of risperidone versus placebo in the treatment of psychosis of Alzheimer's disease. In: Clinical trials journal CNO - CN-00404159. 2002:1-6.
    1. Mintzer J, Greenspan A, Caers I, Van Hove I, Kushner S, Weiner M, et al. Risperidone in the treatment of psychosis of Alzheimer disease: results from a prospective clinical trial. American Journal of Geriatric Psychiatry 2006;14(3):280-91. [DOI: 10.1097/01.JGP.0000194643.63245.8c] - DOI - PubMed
Mintzer 2007 {published data only}
    1. Mintzer JE, Tune LE, Breder CD, Swanink R, Marcus RN, McQuade RD, 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. American Journal of Geriatric Psychiatry 2007;15(11):918-31. [DOI: 10.1097/JGP.0b013e3181557b47] - DOI - PubMed
NCT00287742 2006 {published data only}
    1. A study of the effectiveness and safety of risperidone versus placebo in the treatment of patients with hallucinations and delusions associated with Alzheimer's disease. https://clinicaltrials.gov/show/NCT00287742 2006.
Paleacu 2008 {published data only}
    1. 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 2008;23(4):393-400. [DOI: 10.1002/gps.1892] - DOI - PubMed
RIS‐INT‐83 2003 {published data only}
    1. Johnson, Johnson Pharmaceutical R, Development LLC. Efficacy and safety of a flexible dose of risperidone versus placebo in the treatment of psychosis of Alzheimers disease. A double-blind, placebo-controlled, parallel-group study. Yale open data access (YODA) project 2003.
Schneider 2003 RIS USA 63 {published data only}
    1. Brecher M, Clyde C, Risperidone Study Group. Risperidone in the treatment of psychosis and aggressive behavior in patients with dementia. In: Proceedings of the 8th Congress of the International Psychogeriatric Association: Jerusalem, Israel, August 17-22, 1997 CNO - CN-00713949. 1997:10.
    1. Brecher M. Follow-up study of risperidone in the treatment of patients with dementia: interim results on tardive dyskinesia and dyskinesia severity. In: 11th European College of NeuropsychoPharmacology Congress. Paris, France. 31st October - 4th November 1998. 1998.
    1. Grossman F, Gharabawi G. Elderly patients with dementia and psychosis treated with risperidone. In: Proceedings of the 8th International Conference on Alzheimer's Disease and Related Disorders; 2002 July 20-25, Stockholm, Sweden CNO - CN-00385944. 2002:AbstractNo299.
    1. Grossman F, Okamoto A, Turkoz I, Gharabawi G. Risperidone in the treatment of elderly patients with psychosis of Alzheimer's disease and related dementias. Journal of the American Geriatrics Society 2004;52(5):852-3. - PubMed
    1. Katz I, Brecher M, Clyde C, Napolitano J, Risperidone Study Group. Risperidone in the treatment of psychosis and aggressive behavior in patients with dementia. Proceedings of the 9th Biennial Winter Workshop on Schizophrenia; 1998 Feb 7-13, Davos, Switzerland CNO - CN-00856755 1998;29(1-2):145.
Schneider 2006 CATIE‐AD {published data only}
    1. Davis SM, Koch GG, Davis CE, LaVange LM. Statistical approaches to effectiveness measurement and outcome-driven re-randomizations in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) studies. Schizophrenia Bulletin 2003;29(1):73-80. - PubMed
    1. Nagata T, Shinagawa S, Nakajima S, Plitman E, Mihashi Y, Hayashi S, et al. Classification of neuropsychiatric symptoms requiring antipsychotic treatment in patients with Alzheimer's disease: analysis of the CATIE-AD study. Journal of Alzheimer's Disease 2016;50(3):839-45. [DOI: 10.3233/JAD-150869] - DOI - PubMed
    1. Ozawa C, Roberts R, Yoshida K, Suzuki T, Lebowitz B, Reeves S, et al. Placebo effects in the treatment of Noncognitive symptoms of Alzheimer's disease: analysis of the CATIE-AD data. Journal of Clinical Psychiatry 2017;78(9):e1204-e1210. [DOI: 10.4088/JCP.17m11461] - DOI - PubMed
    1. Rosenheck RA, Leslie DL, Sindelar JL, Miller EA, Tariot PN, Dagerman KS, et al Clinical Antipsychotic Trial of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) investigators. Cost-benefit analysis of second-generation antipsychotics and placebo in a randomized trial of the treatment of psychosis and aggression in Alzheimer disease. Archives of General Psychiatry 2007;64(11):1259-68. [DOI: 10.1001/archpsyc.64.11.1259] - DOI - PubMed
    1. Schneider LS, Ismail MS, Dagerman K, Davis S, Olin J, McManus D, et al. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer's disease trial. Schizophrenia Bulletin 2003;29(1):57-72. - PubMed
Streim 2008 {published data only}
    1. Streim JE, Porsteinsson AP, Breder CD, Swanink R, Marcus R, McQuade R, et al. A randomized, double-blind, placebo-controlled study of aripiprazole for the treatment of psychosis in nursing home patients with Alzheimer disease. American Journal of Geriatric Psychiatry 2008;16(7):537-50. [DOI: 10.1097/JGP.0b013e318165db77] - DOI - PubMed
Tariot 2006 {published data only}
    1. A Protocol No 5077IL/0039: a multicenter, double-blind comparison of efficacy and safety of Seroquel® (quetiapine fumarate), haloperidol, and placebo in the treatment of elderly subjects residing in nursing homes or assisted care facilities and presenting with Alzheimer's dementia and psychoses or other selected psychoses. www.clinicalstudyresults.org 2006.
    1. Tariot P, Schneider L, Katz I, Mintzer J, Street J. Quetiapine in nursing home residents with Alzheimer's dementia and psychosis. In: American Journal of Geriatric Psychiatry. Vol. 10. 2002:93.
    1. Tariot PN, Schneider L, Katz IR, Mintzer JE, Street J Copenhaver M, et al. Quetiapine treatment of psychosis associated with dementia: a double-blind, randomized, placebo-controlled clinical trial Epub 2006 Aug 11; Erratum in: am J Geriatr Psychiatry 2006 Nov;14(11): 988Tariot PN et al. AmericanJjournal of Geriatric Psychiatry 2006;14(9):767-76. [DOI: 10.1097/01.JGP.0000196628.12010.35] - DOI - PubMed
Teri 2000 {published data only}
    1. Teri L, Logsdon RG, Peskind E, Raskind M, Weiner MF, Tractenberg RE, , et al Alzheimer's Disease Cooperative Study. Treatment of agitation in AD: a randomized, placebo-controlled clinical trial. Neurology 2000;55(9):1271-8. - PubMed
Zhong 2007 {published data only}
    1. A multicenter, double-blind, randomized comparison of the efficacy and safety of quetiapine fumarate (SEROQUEL®) and placebo in the treatment of agitation associated with dementia. Clinicaltrials.gov [http://clinicaltrials.gov] 2009.
    1. NCT00621647. [Public title] Seroquel- agitation associated with dementia; [Scientific title] A multicenter, double-blind, randomized, comparison of the efficacy and safety of quetiapine fumarate (SEROQUEL) and placebo in the treatment of agitation associated with dementia. ClinicalTrials.gov [http://clinicaltrials.gov] CNO - CN-00724658 2002.
    1. Tariot PN. Efficacy and tolerability of atypical antipsychotics in agitation and psychosis: research results. In: 158th Annual Meeting of the American Psychiatric Association; 2005 May 21-26; Atlanta, GA CNO - CN-00547351. 2005:No. 31A.
    1. Zhong K, Tariot P, Minkwitz MC, Devine NA, Mintzer J. Quetiapine for the treatment of agitation in patients with dementia. 158th Annual Meeting of the American Psychiatric Association, Atlanta, GA, USA, 21-26 May, 2005 CNO - CN-00548828 2005;abstract NR.726:269.
    1. Zhong KX, Tariot PN, Mintzer J, Minkwitz MC, Devine NA. Quetiapine to treat agitation in dementia: a randomized, double-blind, placebo-controlled study. Current Alzheimer Research 2007;4(1):81-93. - PubMed

References to studies excluded from this review

DeDeyn 1999 RIS‐INT‐24 {published data only}
    1. DeDeyn PP, Rabheru K, Rasmussen MD, Bocksberger JP, Dautzenberg PL, Eriksson S, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999;53(5):946-55. - PubMed
Devanand 1989 {published data only}
    1. Devanand DP, Sackeim HA, Brown RP, Mayeux R. A pilot study of haloperidol treatment of psychosis and behavioral disturbance in Alzheimer's disease. Archives of Neurology 1989;46(8):854-7. - PubMed
Holmes 2007 {published data only}
    1. Holmes C, Wilkinson D, Dean C, Clare C, El-Okl M, Hensford C, et al. Risperidone and rivastigmine and agitated behaviour in severe Alzheimer's disease: a randomised double blind placebo controlled study. International Journal ofGgeriatric Psychiatry 2007;22(4):380-1. [DOI: 10.1002/gps.1667] - DOI - PubMed
Meguro 2004 {published data only}
    1. Meguro K, Meguro M, Tanaka Y, Akanuma K, Yamaguchi K, Itoh M. Risperidone is effective for wandering and disturbed sleep/wake patterns in Alzheimer's disease. Journal of Geriatric Psychiatry and Neurology 2004;17(2):61-7. [DOI: 10.1177/0891988704264535] - DOI - PubMed
NCT00043849 2002 {published data only}
    1. NCT00043849. Treatment of Agitation/Psychosis in Dementia/Parkinsonism (TAP/DAP). https://clinicaltrials.gov/show/NCT00043849 CNO - CN-01496582 2002.
Pollock 2002 {published data only}
    1. Pollock BG, Mulsant BH, Rosen J, Sweet RA, Mazumdar S, Bharucha A, et al. Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. American Journal of Psychiatry 2002;159(3):460-465. [DOI: 10.1176/appi.ajp.159.3.460] - DOI - PubMed
    1. Pollock BG, Mulsant BH, Rosen J, Sweet RA, Mazumdar S, Bharucha A, et al. Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. Research and Practice in Alzheimer's Disease 2003;7:180-6. - PubMed
Shin 2013 {published data only}
    1. Shin CS. A randomized placebo-controlled trial of quetiapine for the treatment of behavioral and psychological symptom of dementia in Alzheimer's disease patients. Journal of the Neurological Sciences 2013;Conference: 21st World Congress of Neurology Vienna Austria. Conference Start: 20130921 Conference End: 20130926. Conference Publication: MISC2 - Journal of the Neurological Sciences. Conference: 21st World Congress of Neurology Vienna Austria. Conference(var.pagings):e294-e295.
Street 2000 F1D MC HGEU {published data only}
    1. Clark WS, Street J, Gannon KS, Sanger T, Tollefson GD, Breier A. Olanzapine in the prevention of psychosis among nursing home patients with behavioral disturbances associated with alzheimer's disease. European Journal of Neurology 1999;6(Suppl 3):115.
    1. Clark WS, Street J, Gannon KS, Sanger T, Tollefson GD, Breier A. Olanzapine in the prevention of psychosis among nursing home patients with behavioral disturbances associated with Alzheimer's disease. Journal of the European College of Neuropsychopharmacology 1999;9(suppl 5):S332.
    1. 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. Journal of Clinical Psychiatry 2001;62(1):34-40. - PubMed
    1. Clark WS, Street JS, Gannon KS, Sanger TM, Tollefson GD, Breier A. Reduction of psychotic symptoms in patients with lewy body like symptoms treated with olanzapine. In: Proceedings of the 9th Congress of the International Psychogeriatric Association; 1999 Aug 15-20, Vancouver, Canada CNO - CN-00858739. 1999:172.
    1. Clark WS, Street JS, Sanger TM, Feldman PD, Breier A. Olanzapine in the prevention of psychosis among nursing home patients with behavioral disturbances associated with Alzheimer's disease. Biological Psychiatry 1999;47(Suppl):S162.
Trequattrini 2003 {published data only}
    1. Trequattrini A, Attala T, Spadoni L, Ciappi F. Olanzapin in the treatment of psychological and behavioral diseases in patients with Alzheimer-type dementia. Giornale di Neuropsicofarmacologia 2003;3:105-13.

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