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

Viktoria Mühlbauer, Ralph Möhler, Martin N Dichter, Sytse U Zuidema, Sascha Köpke, Hendrika J Luijendijk, Viktoria Mühlbauer, Ralph Möhler, Martin N Dichter, Sytse U Zuidema, Sascha Köpke, Hendrika J Luijendijk

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.

Conflict of interest statement

VM: none known

RM: none known

MND: none known

SUZ: none known

SK: none known

HJL: none known

Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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)
14
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
44
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)
49
49
Forest plot (4.3 Somnolence)
50
50
Forest plot (4.4 Extrapyramidal symptoms)
51
51
Forest plot (4.5 Any adverse event)
52
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)
55
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
60
Forest plot (5.2 Psychosis)
61
61
Forest plot (5.3 Somnolence)
62
62
Forest plot (5.4 Extrapyramidal symptoms)
63
63
Forest plot (5.5 Any adverse event)
64
64
Forest plot (5.6 Any serious adverse event)
65
65
Forest plot (5.7 Death)
66
66
Forest plot (5.8 Number of responders for agitation)
67
67
Forest plot (5.9 Number of responders for psychosis)
68
68
Forest plot (5.10 Discontinuation due to adverse events)
69
69
Forest plot (5.11 Discontinuation, any reason)
70
70
Forest plot (5.12 Functioning (ADL))
71
71
Forest plot (5.13 Cognitive function)
1.1. Analysis
1.1. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 1: Agitation
1.2. Analysis
1.2. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 2: Psychosis
1.3. Analysis
1.3. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 3: Somnolence
1.4. Analysis
1.4. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 4: Somnolence (RD)
1.5. Analysis
1.5. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 5: Extrapyramidal symptoms
1.6. Analysis
1.6. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 6: Extrapyramidal symptoms (RD)
1.7. Analysis
1.7. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 7: Any serious adverse events
1.8. Analysis
1.8. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 8: Any serious adverse events (RD)
1.9. Analysis
1.9. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 9: Death
1.10. Analysis
1.10. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 10: Death (RD)
1.11. Analysis
1.11. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 11: Number of responders for agitation
1.12. Analysis
1.12. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 12: Number of responders for agitation (RD)
1.13. Analysis
1.13. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 13: Number of responders for psychosis
1.14. Analysis
1.14. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 14: Number of responders for psychosis (RD)
1.15. Analysis
1.15. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 15: Discontinuation due to adverse events
1.16. Analysis
1.16. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 16: Discontinuation due to adverse events (RD)
1.17. Analysis
1.17. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 17: Discontinuation (any reason)
1.18. Analysis
1.18. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 18: Discontinuation (any reason) (RD)
1.19. Analysis
1.19. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 19: Functioning (ADL)
1.20. Analysis
1.20. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 20: Cognitive function
1.21. Analysis
1.21. Analysis
Comparison 1: Typical antipsychotics versus placebo, Outcome 21: Carer burden
2.1. Analysis
2.1. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 1: Agitation
2.2. Analysis
2.2. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 2: Psychosis
2.3. Analysis
2.3. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 3: Somnolence
2.4. Analysis
2.4. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 4: Extrapyramidal symptoms
2.5. Analysis
2.5. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 5: Serious adverse events
2.6. Analysis
2.6. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 6: Death
2.7. Analysis
2.7. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 7: Number of responders for agitation
2.8. Analysis
2.8. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 8: Number of responders for psychosis
2.9. Analysis
2.9. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 9: Discontinuation due to adverse events
2.10. Analysis
2.10. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 10: Discontinuation (any reason)
2.11. Analysis
2.11. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 11: Functioning (ADL)
2.12. Analysis
2.12. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 12: Cognitive function
2.13. Analysis
2.13. Analysis
Comparison 2: Haloperidol versus placebo, Outcome 13: Carer burden
3.1. Analysis
3.1. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 1: Agitation
3.2. Analysis
3.2. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 2: Psychosis
3.3. Analysis
3.3. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 3: Somnolence
3.4. Analysis
3.4. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 4: Somnolence (RD)
3.5. Analysis
3.5. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 5: Extrapyramidal symptoms
3.6. Analysis
3.6. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 6: Extrapyramidal symptoms (RD)
3.7. Analysis
3.7. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 7: Any adverse event
3.8. Analysis
3.8. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 8: Any adverse event (RD)
3.9. Analysis
3.9. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 9: Any serious adverse event
3.10. Analysis
3.10. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 10: Any serious adverse event (RD)
3.11. Analysis
3.11. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 11: Death
3.12. Analysis
3.12. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 12: Death (RD)
3.13. Analysis
3.13. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 13: Number of responders for agitation
3.14. Analysis
3.14. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 14: Number of responders for agitation (RD)
3.15. Analysis
3.15. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 15: Number of responders for psychosis
3.16. Analysis
3.16. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 16: Number of responders for psychosis (RD)
3.17. Analysis
3.17. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 17: Discontinuation due to adverse events
3.18. Analysis
3.18. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 18: Discontinuation due to adverse events (RD)
3.19. Analysis
3.19. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 19: Discontinuation (any reason)
3.20. Analysis
3.20. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 20: Discontinuation (any reason) (RD)
3.21. Analysis
3.21. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 21: Functioning (ADL)
3.22. Analysis
3.22. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 22: Cognitive function
3.23. Analysis
3.23. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 23: Cognitive function (single study)
3.24. Analysis
3.24. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 24: Health‐related quality of life
3.25. Analysis
3.25. Analysis
Comparison 3: Atypical antipsychotics versus placebo, Outcome 25: Time spend providing care (caregiver)
4.1. Analysis
4.1. Analysis
Comparison 4: Risperidone versus placebo, Outcome 1: Agitation
4.2. Analysis
4.2. Analysis
Comparison 4: Risperidone versus placebo, Outcome 2: Psychosis
4.3. Analysis
4.3. Analysis
Comparison 4: Risperidone versus placebo, Outcome 3: Somnolence
4.4. Analysis
4.4. Analysis
Comparison 4: Risperidone versus placebo, Outcome 4: Extrapyramidal symptoms
4.5. Analysis
4.5. Analysis
Comparison 4: Risperidone versus placebo, Outcome 5: Any adverse event
4.6. Analysis
4.6. Analysis
Comparison 4: Risperidone versus placebo, Outcome 6: Any serious adverse event
4.7. Analysis
4.7. Analysis
Comparison 4: Risperidone versus placebo, Outcome 7: Death
4.8. Analysis
4.8. Analysis
Comparison 4: Risperidone versus placebo, Outcome 8: Number of responders for agitation
4.9. Analysis
4.9. Analysis
Comparison 4: Risperidone versus placebo, Outcome 9: Number of responders for psychosis
4.10. Analysis
4.10. Analysis
Comparison 4: Risperidone versus placebo, Outcome 10: Discontinuation due to adverse events
4.11. Analysis
4.11. Analysis
Comparison 4: Risperidone versus placebo, Outcome 11: Discontinuation (any reason)
4.12. Analysis
4.12. Analysis
Comparison 4: Risperidone versus placebo, Outcome 12: Cognitive function
4.13. Analysis
4.13. Analysis
Comparison 4: Risperidone versus placebo, Outcome 13: Functioning (ADL)
4.14. Analysis
4.14. Analysis
Comparison 4: Risperidone versus placebo, Outcome 14: Health‐related quality of life
4.15. Analysis
4.15. Analysis
Comparison 4: Risperidone versus placebo, Outcome 15: Time spend providing care (caregiver)
5.1. Analysis
5.1. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 1: Agitation
5.2. Analysis
5.2. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 2: Psychosis
5.3. Analysis
5.3. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 3: Somnolence
5.4. Analysis
5.4. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 4: Extrapyramidal symptoms
5.5. Analysis
5.5. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 5: Any adverse event
5.6. Analysis
5.6. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 6: Any serious adverse event
5.7. Analysis
5.7. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 7: Death
5.8. Analysis
5.8. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 8: Number of responders for agitation
5.9. Analysis
5.9. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 9: Number of responders for psychosis
5.10. Analysis
5.10. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 10: Discontinuation due to adverse events
5.11. Analysis
5.11. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 11: Discontinuation (any reason)
5.12. Analysis
5.12. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 12: Functioning (ADL)
5.13. Analysis
5.13. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 13: Cognitive function
5.14. Analysis
5.14. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 14: Cognitive function (single study)
5.15. Analysis
5.15. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 15: Health‐related quality of life
5.16. Analysis
5.16. Analysis
Comparison 5: Quetiapine versus placebo, Outcome 16: Time spend providing care (caregiver)

Source: PubMed

3
Tilaa